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*Corresponding author: E-mail: drasv@ymail.com; 
 
 
 

Asian Journal of Immunology 
 
3(1): 233-252, 2020; Article no.AJI.58422 
 

 
 

 

 

Acute Immune Mediated Lung Injury in COVID 19: 
A Review 

 
A. S. V. Prasad1* 

 
1
Department of Internal Medicine, Gandhi Institute of Technology and Management, Rishikonda, 

Visakhapatnam, India. 
 

Author’s contribution 
 

The sole author designed, analysed, interpreted and prepared the manuscript. 
 

Article Information 
 

Editor(s): 
(1) Dr. Cynthia Aracely Alvizo Báez, Autonomous University of Nuevo Leon, Mexico. 

Reviewers: 
(1) Ritika Gupta, India. 

(2) Abioye, Adesoye Idowu, University of Ilorin, Nigeria. 
Complete Peer review History: http://www.sdiarticle4.com/review-history/58422 

 
 
 

Received 01 June 2020  
Accepted 16 June 2020 
Published 23 June 2020 

 
 

ABSTRACT 
 

There are many gaps in our present understanding of the of the SARS CoV 2 related matters like 
its PAMPs,(pathogen associated molecular patterns),antigenic profile, immune evasive 
mechanisms and also other host related matters, like PRR s(pattern recognizing receptors) and the 
deranged host defense mechanisms, that cause self-damage. These constraints come in way of 
accurately delineating the pathogenesis of COVID19 lung disease. Hence is the speculative nature 
of any concept trying to explain the same. An integrated approach is embarked upon, taking into 
account the known clinical, radiological, laboratory, and autopsy findings, in search of clues that 
may suggest a possible mechanism, that explains the underlying lung damage in COVID 19. It is 
seen that no single mechanism or syndrome could explain fully the pathology and pathogenesis of 
lung damage in COVID19. Hence, multiple mechanisms consistent with each known facet of the 
pathology are explored. Thus the inflammatory damage of the alveolar tissue is sought to be 
explained by the3 complement activation pathways i.e. the alternative pathway, the MBL/Lectin 
pathway/ and Tissue factor/extrinsic pathway(of the classical complement activation), the contact 
cascade involving the kallikrein-kinin pathway, and the cytokine mediated pro and anti inflammatory 
mechanisms. The vascular pathology like hemorrhages and small blood vessel micro-thrombi as 
observed at autopsy , are viewed from the point of view of simple activation of the coagulation 
cascade to small vessel vasculitis (leucocytoclastic vasculitis) and coagulative micro angiopathy. 
Besides, the role of TM-PC-EPCR SYSTEM (Thrombomodulin-Protein C-EPCR System) is 
explored. The points in favour and against of each of the above are discussed.The central role 
played by the macrophage polymorphism is focused in the context of the simultaneous presence of 

Review Article 



 
 
 
 

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234 

 

active inflammation in the lung tissue and the interstetium and healing by interstitial fibrosis, seen in 
the lungs of COVID 19 patients. The role played by the other humoral and cellular elements of both 
innate and adaptive immunity is briefly reviewed. The uniqueness and diversified features of 
COVID 19 lung pathology, suggests two things - that the immune mediated damage seems more 
probable than could be explained by the viral infectivity and that the pathology seems to stem from 
a mixture of different underlying and overlapping syndromes. Hence, the author prefers to call all 
the COVID 19 related features of lung pathology as “Acute immune mediated Lung injury". (AILI) 
than trying to bunch them under a single syndrome.  
 

 

Keywords: Pathogen associated proteins (PAMPs); pathogen recognizing receptors (PRRs) 
complement; cytokines; phagocytosis; antibody; ARDS; immune evasion; capillaritis; 
microangiopathy. 

 

1. INTRODUCTION 
 

The lung pathology and pathogenesis of covid 
19, is elusive and hence remained speculative, 
till date. Described originally as a ‘pneumonia-
like’ condition, similar to one caused by SARS 
CoV 1 (2003) and MERS CoV, (2011), which are 
members of the same family of Corona virus. 
The former was less severe but caused 
pandemic and the later was 34% more 
severe,mortality-wise , but remained confined to 
middle east mostly. The COVID 19, thus 
resembled more of SARS 1 and hence the virus 
is named SARS Cov 2. In due course of time, the 
postscript, ‘like’ is dropped and the syndrome 
has come to be called ‘COVID 19 pneumonia’, 
contrary to the facts. The opinions as to the 
cause of COVID 19 induced lung damage varied 
from ARDS, SHLH (secondary hemophagocytic 
lymphohistiocytosis) and Cytokine storm from the 
clinical point of view and ‘interstitial pneumonia’ 
from radiological point of view. The autopsy 
findings raise suspicion of capillarites (small 
blood vessel vasculitis) to coagulative 
microangiopathy. It is felt that the clinical as well 
as laboratory, radiological and autopsy data if 
taken together sheds some light as to the exact 
lung pathology and pathogenesis of COVID 19 
lung disease. Hence these aspects are briefly 
reviewed in search of clues to the lung 
pathology/pathogenesis of COVID 19.  
 

2. CLINICAL DATA 
 

2.1 Pneumonia- Like Condition of COVID 
19 vs ARDS  

 

Li, X., Ma, X [1] has elaborately discussed the 
matter and could make out some differences 
between the two conditions. Peter G Gibson et 
al. 2020) [2] have to say " We are familiar with 
ARDS, however when it occurs as part of 
COVID-19, it has different features and there 
remain, unanswered questions". Wu C, Chen X, 

Cai Y, Xia J, Zhou X, Xu S (2020) suggest that 
among the patients affected, the pneumonia-like 
process of COVID 19. Unto 20% only develop 
pneumonia of which, about 3 to 4% develop 
severe form necessitating ventilator support. 
~50% develop hypoxemia by day 8. Severe 
illness and cytokine release syndrome appear to 
develop mostly within 5–10 days after the onset 
of symptoms in susceptible patients. ARDS- like 
clinical picture is suggested to develop in 42% of 
patients presenting with COVID-19 pneumonia, 
and 61-81% of those requiring ICU care [3]. 
Puah SH et al. report that COVID-19 ARDS 
follows a predictable time course over days, with 
median time to incubation period of 8.5 days 
after onset of symptom in Singaporean patients 
[4]. Not all COVID 19 patients suffer pneumonia- 
like syndrome. Even though alI of those who 
develop this very few of them develop severe 
respiratory distress, necessitating ventilator 
support. Most of them have comorbid diseases 
and constitute to the 2 to 3% mortality observed. 
The autopsy findings which suggested ARDS are 
- the firm, heavy lung filled with fluid and 
presence on bits of hyaline membrane in the 
lungs. Severe illness and cytokine release 
syndrome appear to develop mostly within 5–10 
days after symptom onset in susceptible patients. 
Not all COVID 19 patients suffer pneumonia like 
syndrome. Even though those who develop this 
very few develop severe respiratory distress, 
necessitating ventilator support. Most of them 
have comorbid diseases and constitute the 2 to 
3% mortality observed. The autopsy findings 
which suggested ARDS are the firm, heavy lung 
filled with fluid and presence on bits of hyaline 
membrane in the lungs. Peter G Gibson et al 
opine that most of the COVID-19 patients, meet 
the Berlin definition (2012) for ARDS. All of them 
have present with an acute clinical emergency, 
with bilateral opacities in the lung imaging, gas 
exchange abnormalities, and their disease can't 
be explained by heart failure or volume overload. 
The ARDS Berlin criteria defined that for a 



 
 
 
 

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patient to be diagnosed as having ARDS, the 
onset must be within 1 week of a known clinical 
insult or new or worsening respiratory symptoms. 
[5], Wang et al. [6] reported median timed onset 
of ARDS, as 8.0 days, Zhou et al. [7] as 12 days. 
Chen et al. [8] and Guan et al. [9] did not report 
the onset of ARDS. The lowest median time 
reported is 4 days from the onset of first 
symptom. The main departure from ARDS and 
SARS CoV2 pneumonia is the preserved lung 
compliance in face of severe hypoxia, and poor 
oxygenation without increased work of breathing, 
which are not seen in ARDS. It is also seen that 
ARDS developed in some COVID 19 patients 
after they have been put on ventilator, sparking 
speculation as to whether such development is 
due to natural progression of the COVID 19 or 
ventilator induced. Robba C, Battaglini D 
Patroniti N [10] et al. suggested 3 phenotypes of 
patients, basing on their CT findings of lungs in 
Covid 19 (discussed under imaging features, 
below). They opine that not all cases of COVID 
lung involvement resemble ARDS. Gattinoni et 
al. [11] described two distinct phenotypes, Type 
L and Type H (Type 1 and Type 2). Type L 
disease, is characterized by normal lung 
compliance and gas volume in the presence of 
hypoxemia. These patients may improve, or they 
may worsen. About 20% to 30% of patients had 
or evolved to Type H disease, characterized by 
worse lung compliance and increased edema 
and lung weight. "The transition from Type L to 
Type H may be due to the evolution of the 
COVID-19 pneumonia on one hand and the 
injury attributable to high-stress ventilation on the 
other". 
 
SARS of COVID 2 vs (sHLH)/CYTOKINE 
Storm: Macrophage activation syndrome (MAS), 
also known as secondary haemo phagocytic 
lympho histocytosis (SHLH) or Cytokine storm is 
distinguished by: 
 

1. Absent haemophagocytosis 
2. Lower ferritin levels. 
3. Coagulopathy not being due to liver 

synthesized factors. 
4. DIC is seen as a terminal event in some 

COVID 19 patients only even though hyper-
cytokinemia.  

 

2.2 Radiology / Imaging Data 
 
The imaging technics have high sensitivity of 
about 97% when tested within 5 days of RT- 
PCR became positive and still can detect the 
changes as early as 3 days, but 56% are found 

to be normal when imaged in 2days of patient 
becoming COVID 19 positive. Thus the 
sensitivity of imaging the lungs in COVID 19, is a 
function of time of doing the test. C. Hani M.-P. 
Revel et al. (2020) extensively reviewed not only 
the CT findings of COVID 19, but other causes of 
differential diagnosis of the typical ground glass 
shadows seen in Imaging of COVID 19 lung [12]. 
Some of the important radiological findings are 
presented below. For differential diagnosis the 
readers may refer to the reference suggested. 
 

1. Bilateral ground glass appearance which 
are round in 50% cases. They are called 
COVID balls  

2. Areas of focal consolidation. 
3. Crazy paving pattern resulting from 

intralobular reticulations. 
4. Late signs: Signs suggesting organizing 

pneumonia.  
 

1. Linear consolidations 
2. Reverse halo sign i.e., areas of ground-

glass surrounded by peripheral 
consolidation. 

 
Study by Salehi et al. revealed that the 
frequencies of the different CT abnormalities 
were as follows: GGO (central ground glass 
opacity) was observed in 88.0% of patients, 
consolidation in 31.8%, bilateral involvement in 
87.5% and peripheral distribution in 76.0% of 
patients [13]. Guan CS, et al. (2020) assert that 
“ground-glass opacities may be due to mild 
oedema of the alveolar septi, hyperplasia of the 
interstitium, partial filling of airspaces, or a 
combination of these features. Besides, the 
crazy-paving pattern may correlate with 
hyperplasia of interlobular and intralobular 
interstitia” [14]. 
 

The two radiological features still alluding 
explanation are-  
 

1. Peripheral and subpleural distribution  
2. Bilateral lower lobe involvement  

 

Autopsy findings: Xu, L. Shi, Y. Wang, et al. 
[15] described in detail, the post-mortem findings 
of COVID 19. 
 

Gross pathology: The lungs are firm and 
increased in weight and laden with secretions 
and exudate. Both the surface of lung and the cut 
section showed, patchy areas of haemorrhage. 
 

Microscopic findings: These can be grouped 
as cellular, vascular and other features. 



 
 
 
 

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236 

 

The cellular exudate consisted of CD4+ and 
CD8+ lymphocytes in the lung tissue and 
interstetium and with some perivascular 
collection. Also present are platelet cells, 65+ 
atypical megakaryocytes and desquamated type 
2 pneumatocytes showing cytopathic effect. 
Neutrophils are absent except in the immuno-
suppressed case. 
 
Vascular features: Small blood vessels 
(capillaries) are found to be thickened, with 
oedematous walls, dilated and showed increased 
permeability with consequent seepage of plasma 
into the lung tissue. There is lymphocytic 
accumulation around the capillaries and micro- 
throbi inside the capillaries. The bigger 
pulmonary vessels near hilum are not affected.  
 

2.3 Other Autopsy Findings 
 

1. Focal presence of haemorrhagic. Patches, 
both in gross appearance and cut section 
of lung. 

2. Focal greyare as of consolidation  
3. Presence of clots in the lung tissue. 
4. Scattered hyaline membrane and fibrin 

threads. 
 

3. LABORATORY DATA 
 

The laboratory tests found to be positive in 
COVID 19 also give some clues as to the 
underlying mechanisms involved in the pathology 
and parthenogenesis of COVID 19, if interpreted 
properly. The involvement of liver, kidney, and 
heart is indicated by the increase in lab findings 
pointing in that direction. Probably they represent 
subclinical involvement of the organs concerned, 
as overt manifestation of their involvement is 
seen only in a few of the patients and some in 
the later phase than earlier phage of the disease 
evolution. Leuko-erythroblastic reaction 
reported by some is a finding that needs to be 
investigated.The same is explained as probable 
involvement of bone marrowis the increased 
prothrombin time (PT) indicates the involvement 
of the extrinsic coagulative pathway as the cause 
of thrombotic phenomena observed in the small 
blood vessels at autopsy. The presence of D- 
dimers, FDP, to the underlying thrombolytic 
(fibrinolytic) process involving capillaries of the 
lungs. Of interest, is the observation of 
lymphopenia whereas lymphocytosis is 
commonly seen in all other viral infections. The 
lymphopenia is connected to increased severity / 
mortality in COVID 19 patients. The lab 
parameters also vary as the disease progresses. 
The platelets, the neutrophils and CD8+T cells 

are found to be normal in patients not admitted to 
ICU, where as neutrophilia and low platelets and 
CD 8+ T cells counts are seen in ICU pts. The 
iCU patients have increased risk of complications 
and mortality. The risk stratification of COVID 19 
pneumonia patients has been analyzed by 
Janusz Jankowski t al. The Lab tests found 
positive in COVID 19 patients irrespective of their 
stage of disease, and what they suggest are 
tabulated and presented in Appendix 3. 
 

4. DISCUSSION 
 
Any envisaged pathogenic mechanism should 
explain all the clues available from the clinico-
pathological data reviewed above. To put it 
succinctly, such concept has a clear beginning 
(in the form of virus-host interaction) a clear 
destination (the pathology elucidated by autopsy 
findings), a clear source (the normal physiological 
mechanisms). What is to be clinched is the 
means by which the normal physiology is turned 
into pathology in the context of COVID 19. The 
gaps in the present understanding of the issues 
involved, leaves no alternative than to ‘hazard a 
guess ‘as to the actual pathogenesis of the 
disease. 

 
The viral factors: The genome of SARS CoV 2 
encodes four main structural proteins: Spike (S), 
(which has S1 and S2 sub-units) envelope (E), 
nucleocapsid (N) and membrane (M) proteins .It 
is known that the SARS CoV 2 attaches through 
spike protein to the cell surface negotiate the 
ACE 2 receptor of the host cell, to gain entry into 
the body. It is even suggested that by 
internalizing the ACE 2 receptor down 
regulates its protective lung function, prevailing 
under normal physiological conditions The 
difference in degree of severity and infectivity 
seen between the different countries and within 
certain states of a country, lead to the conclusion 
that there are different strains of the COVID 19 
virus and that the virus suffered nearly 200 
mutations so far. The worldwide distribution 
belonged to strain types A2 a, A3, B and BB4. 
The CCMB (Centre for cellular and molecular 
Biology), Hyderabad, India, found that a different 
'cluster of strains’ , named as “Clade A3i", 
responsible for infection in different states in 
India, some of which registered more cases / 
mortality ( Maharashtra, Gujarat , Tamil nadu and 
Delhi) than others. (Vide the pre-publication 
press note released on 3

rd
 June 2020). 

 
The host factors: The fight between the virus 
and the defence begins with the virus presenting 



 
 
 
 

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its conserved molecular signature expressed on 
its surface (PAMPs) which the defence cells 
recognize by special receptors located on their 
surface (PRRs) 
 
PPRs and PAMPs: PPRs (pattern recognizing 
receptors) are proteins which recognize PAMPs 
(pattern associated molecular patterns), a 
conserved specific sequence which the 
pathogens display on their surface (epitopes) for 
the recognition by the PRRs of the effector 
immune cells The details of the PAMPs and 
PRRs in case of COVID 19 are still not fully 
elucidated. Some authors dealing with this 
aspect, quote the information available on the 
SARS CoV 1, which holds about 79% homology 
in antigenic structure with SARS CoV 2. The 
sofar known PRRs and PAMPs are listed in 
appendix 1, with the assumption that any of 
these might be found relevant to the context of 
Caved 19, by future research. The possible 
interactive pathway between the PAMPs and 
PRRs is depicted in Appendix 2. 

 
The recognized viral surface antigens are 
presented by the antigen presenting cells (ARC) 
of the effect or immune cellular elements after 
being processed by MHC class 2 elements. Here 
also clarity as to details are lacking. This is 
followed by the humoral or cellular response by 
both innate and adaptive immunity systems, the 
sole purpose being destruction and elimination of 
the virus. Here also gaps in current knowledge is 
considered as hindrance to the understanding           
of actual happening in the context of COVID 19 
pathogenicity. The virus probably and 
ingeniously turns the host’s defense, against the 
host itself by various subversive actions, to far 
then their own survival and multiplication, 
resulting in immune mediated injury to host 
tissues The COVID 19 lung pathology should be 
considered in these lines, as a fallout of the 
aberrant immune response. The reported 
damage to the lungs is belied to start within a 
week or so of the patient becoming symptomatic, 
the role played by the innate immune 
mechanisms assume importance, as they first 
encounter the virus. It is only after a week or so, 
that the adaptive immune mechanisms come to 
fore. So, in the later course of the disease, both 
the immunity mechanisms may supplement or 
compliment or act independently to sustain the 
immunological damage. The humoral and cellular 
components of both system play important roles 
but some play greater role than the others. So 
the more important elements are discussed in 
detail while with due consideration to the 

subsidiary role played by the other elements, 
discussion is limited to a brief consideration 
about them. The discussion is in accordance with 
the importance of the role each element of both 
the systems. The discussion is limited only to the 
destructive immune mechanisms of both the 
immunity system and nothing will be referred to 
the protective role they play. 
 

4.1 The Role of Innate Immune System 
 
4.1.1 Role of complement: The alternative 

pathway: 
 
Joshua M. Thurman and V. Michael Holers, et al. 
[16] has reviewed this matter: 
 

1. The alternative pathway is capable of auto 
activation because of a process termed 
“tick over” of C3 [17]. 

2. Tick over generates a conformationally 
altered C3, designated C3(H2O).  

3. This is capable of binding, the factor B  
4. Factor D cleaves Factor B into Ba and Bb. 
5. Bb remains bound to C3(H2O) to form 

C3(H2O)Bb.( fluid-phase C3-convertase).  
6. This alternative pathway C3-convertase, 

although only produced in small amounts, 
can cleave multiple C3 proteins into C3a 
and C3b. 

7. The complex is believed to be unstable 
until it binds properd in, a serum protein.  

8. The addition of properd in forms the 
complex C3bBbP, a stable compound. 

9. This binds an additional C3b to form 
alternative pathway C5-convertase. 

10. The C5-convertase of the alternative 
pathway consists of (C3b)2BbP (sometimes 
referred to as C3b2Bb).  

11. After this step, the complement system 
follows the same path regardless of the 
means of activation (alternative, classical, 
or lectin).  

12. C5-convertase cleaves C5 into C5a and 
C5b.  

13. C5b binds sequentially to C6, C7, C8 and 
then to multiple molecules of C9 to form 
membrane attack complex. (MAC). 

 
Regulatory proteins that disrupt the 
complement activation process: Since C3b is 
free and abundant in the plasma, it can bind to 
either a host cell or a pathogen surface antigen. 
Thus, the complement activation can kill a virus 
infected cell or even the healthy host cells. To 
prevent the host cell damage, there are several 
inbuilt inhibitory mechanisms operating under the 



 
 
 
 

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238 

 

physiological conditions. Conversely the virus 
may subvert the very same mechanisms to 
sustain its own survival as seen in case of some 
the virus (vide infra). 
 

4.1.2 Physiological inhibitors of the 
alternative complement cascade 

 

o Complement Receptor 1 (CR1) or CD35) 
and DAF (decay accelerating factor also 
known as CD55) completes with Factor B in 
binding with C3b on the cell surface and can 
even remove Bb from an already formed 
C3bBb complex. 

o Complement factor(CF), a plasma protease, 
prevents the formation of a C3 
convertasewhich Cleaves C3b into its 
inactive form, iC3b. Factor I requires a C3b-
binding protein cofactor such as 
complement factor H, CR1, or Membrane 
Cofactor of Proteolysis (MCP or CD46) [18]. 

o Complement Factor H can inhibit the 
formation of the C3 convertase by 
competing with factor B for binding to 
C3C3bl [19] accelerate the decay of the C3 
convertase. [20] and act as a cofactor for 
Factor I-mediated cleavage of C3b [21]. 
Complement factor H preferentially binds to 
vertebrate cells (because of affinity for sialic 
acid residues), allowing preferential 
protection of host (as opposed to bacterial) 
cells from complement-mediated damage. 

o CFHR5 (Complement Factor H-Related 
protein [22]. 

 

Immune evasion by the virus: The lipid bi-layer 
membrane of COVID 19 is cited as the cause of 
failure of host’s immune system. Beyond this 
there is no data as to how actually SAzRScoV2 
evades the immune system. Other others have 
narrowed the analogy with SARS CoV 1 and 
MERS CoV. The author cites few examples of 
other virus whose immune evading mechanism 
was studied and reported. The future research is 
expected to throw more light on this aspect. 
 

4.1.3 Illustrations of how some virus subvert 
the defence against self cell destruction 

 

1. Synthesis of new regulatory proteins 
 

illustration: West Nile virus synthesizes two 
isoforms of NS1 protein to regulate C3. Soluble 
NS1 increases Factor I-mediated cleavage of 
C3b to iC3b while the cell surface-bound NS1 
decreases deposition of C3b and MAC [23]. 
 

2. Incorporation of the host complement 
regulatory proteins to virions: To evade 

complement-mediated destruction , human 
immunodeficiency virus-1 (HIV-1), human 
T-lymphotropic virus-1 (HTLV-1) and 
human cytomegalovirus (HCMV) 
incorporate the complement controlled 
proteins CD55 and CD59 into their virions 
to circumvent the complement response 
[24,25]. 

 

3. Prevention of the cell lysis by inhibiting 
the remainder of the complement 
cascade 

 

Illustration: HIV enters human CD4+ T cells 
through complement receptors. HIV gp41 and 
gp120 proteins activate complement through the 
classical and lectin pathways, respectively. At the 
same time, the above two proteins inhibit MAC 
formation by recruiting Factor H and CD59 to the 
surface of the virally-infected host cell to abolish 
complement-mediated lysis [26]. 
 

4. Modulate cytokine expression to induce a 
pro-coagulant state 

 

Illustration: Mediated by IL-1(interleukin) , 
TNFα,(tumour necrosis factor) and IL-6, Marburg 
virus, Ebola virus and Hanta virus induce tissue 
factor expression on the endothelial surface 
[27,28]. 
 

5. Use coagulation factors to enhance 
viral binding and replication 

 

Illustration: Human species a adenovirus-18 
(HAdV-18) and 31(HAdV-31). It is known that the 
innate immune reaction recruits the alternate 
complement activation pathway and the adaptive 
immune response involves the classical 
complement activation pathway. There is a third, 
the lectin pathway. The alternate complementary 
pathway starts with cleaving of C3. The classical 
pathway and the lectin pathway both converge 
on production of C3 by a loop.  
 

4.1.4 Complement mediated immune damage 
 

4.1.4.1 Explanation for interstitial pneumonia in 
lung pathology 

 

1. C3 is cleaved into C3b(catalytic fragment) 
and C3bi (non catalytic fragment). Further 
events may follow either of the following 
pathways. 

2. The C3i pathway: C3bi is bound to CR 3 
(CD11b/CD18), integrin αMβ2) receptor of 
the macrophage.  

3. Affinity modulation of macrophage 
integrins is sufficient to allow binding of 



 
 
 
 

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239 

 

opsonized particles, but increased diffusion 
to allow clustering is required in order to 
activate phagocytosis, which is facilitated 
by cytokines IL-4, M-CSF, TNF-α and GM-
CSF. 

 

C3b pathway: This catalytic fragments continues 
the cascade of alternate complement activation 
pathway with ultimate production of MAC 
Complex which cause the lysis and death of the 
infected cell including the virus. 
 

The complement receptor activated stimulation 
will not elicited inflammatory reaction as it cannot 
recruit the pro-inflammatory cytokines and 
chemokines. It could be inferred from the 
polymorphism (see below) exhibited by the 
alveolar macrophages that the complement 
mediated perhaps stimulates the alternatively 
activated M2 type macrophages which are 
known to be anti inflammatory in response. This 
could come as handicap to the host because, M2 
type stimulation also stimulates the extracellular 
matrix protein, collagen, which produces 
interstitial fibrosis as seen in the COVID 19 lung. 
Thus one of the pathological / radiological  
feature of interstitial pneumonia/ fibrosis is 
explained.  
 
Secondly since this inhibits the expression of the 
inflammatory mediated M1 type macrophages. 
Absence of inflammatory stimulus may make the 
pt in whom this pathway acts asymptomatic but 
yet the lung damage in the form of interstitial 
fibrosis progresses. It is known that the 
symptoms of COVID 19 are due to inflammatory 
response mounted by the body of the host-
patient. 
 

Role of Tissue factor(TF)/(extrinsic) pathway 
in the pathogenesis of COVID 19: 
 

 The increase PT (prothrombin time) and 
injury to subendothelial tissues by cytokine 
induced vascular damage implicate a role 
of this pathway in the coagulopathy seen in 
COVID 19. Tissue factor(extrinsic) path 
way: 

 Tissue factor/platelet- thromboplastin/ 
factor3/ CD 135. It is produced by sub 
endothelial cells and leukocytes. Injury to 
sub endothelial cells/ platelets releases 
this factor which initiates the coagulation 
process. In combination with factor V11, it 
activates factor X to factor Xa. The (tissue 
factor pathway inhibitor (TFPI) is a 
protease present in the ECs inhibits the TF 
and is a natural anticoagulant. 

TF, produced by sub-endothelial cells and 
leukocytesInjury to sub-endothelial cells/ 
platelets initiates the coagulation process. In 
combination with factor V11, it activates factor X 
to factor Xa. The (tissue factor pathway 
inhibitor (TFPI) is a protease present in the ECs 
inhibits the TF and is a natural anticoagulant. 
The TF pathway may be recruited by the 
cytokine induced damage of the vasculature 
orInjury to the platelets which consequently 
release the TF. This is supported by the 
immature megakaryocytes(indicating rapid 
turnover/distruction of the platlets) found in the 
microscopic findings of autopsy. 

 
The role of MBL (mannose binding leptin) / 
Lectin pathway: The activation of complement 
via the mannan-binding lectin (MBL) pathway is 
initiated by the MBL complex consisting of the 
carbohydrate binding molecule, MBL, two 
associated serine proteases, MASP-1(mannose-
associated serine protease) and MASP-2, and a 
third protein, MASP-19. When the carbohydrate-
recognising heads of MBL bind to specifically 
arranged mannose residues on the surface of a 
pathogen, MASP-1 and MASP-2 are activated to 
cleave complement components C4 and C2 into 
C4a, C4b, C2a, and C2b. In f, two smaller MBL-
associated proteins (MAPs) are found in complex 
with MBLC4b2a3b, the C3 esterase so formed 
carries onwards the complement cascade in the 
same way as the alternative pathway described 
in detail above. The involvement of the lectin 
pathology is supported by the finding reported by 
Cynthia Magro (2020)of deposits of terminal 
complement components C5b-9 (membrane 
attack complex), C4d, and mannose binding 
lectin (MBL)-associated serine protease 
(MASP)2, in the microvasculature, Leptin is a 
glycoprotein and the SARS CoV has glycoprotein 
antigens which may be recognized by the C -
Lectin receptors (PPRs) present on the surface 
of the macrophages and other effector cells 
,leading to their activation leptin can modulate 
the response to an inflammatory challenge by 
altering production of proinflammatory and anti-
inflammatory cytokines and may also affect 
cytokine signalling by a variety of mechanisms, 
including induction of SOCS-3.(suppressor of 
cytokine signalling). 

 
4.1.5 Explanation for vascular changes in 

lung pathology: 
 
These can be explained by activation of                     
the contact cascade or by cytokine induced 
damage. 

https://en.m.wikipedia.org/wiki/Complement_component_4
https://en.m.wikipedia.org/wiki/Complement_component_2


 
 
 
 

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240 

 

 Contact cascade 
 

1) Factor XII (FXII; Hageman factor) of the 
contact system is proteolyticallycleaved to 
FXIIa by negatively charged surfaces of 
damaged cells, and also activated platelet 
plasma membrane. 

2) FXIIainitiates the coagulation cascade 
leading to clot formation. 

3) cleaves prekallikrein to kallikreinfor 
subsequent release of bradykinin.  

4) Through an endothelial G-coupled receptor 
(bradykinin receptor 1; BKR1), bradykinin 
induces vasodilation, neutrophil 
chemotaxis and vascular permeability  
[29]. 

 

 The cytokine induced Vascular changes 
in the lungs: Alexander H. Sprague and 
Raouf A. Khalil et al. [30] and. Marlies Van 
de, Wouwer Désiré Colle, Edward M. 
Conway metal [31] have extensively 
reviewed this subject matter. Interested 
readers may refer these articles for full 
details.  
 

Cytokines are a diverse group of soluble short 
acting proteins, glycoproteins and peptides 
produced by various immune cells and vascular 
cells, activate specific receptors and modulate 
the functions of many cells and tissues. 
 

 Cytokines include tumour necrosis 
factors, interleukins, lymphokines, 
monokines, chemokines, interferons, 
colony stimulating factors, and 
transforming growth factors. 

 Cytokines are produced by macrophages, 
T cells and monocytes, platelets, 
endothelial cells (ECs) and vascular 
smooth muscle cells (VSMCs).  

 Cytokines elicit inflammatory response by 
interacting with specific receptors on various 
cell types and activate JAK-STAT, (Janus 
kinase/signal transducers and activators of 
transcription NF-κB, and SMAD 
(Suppressor of Mothers Against 
Decapentaplegic. Miscellaneous)signalling 
pathways leading to cell adhesion, 
permeability and apoptosis 

 Cytokines also interact with mitochondria 
to increase the production of reactive 
oxygen species.  

 Cytokine-induced activation of these 
pathways in ECs modifies the production/ 
activity of vasodilator mediators such 
nitric oxide, prostacyclin, endothelium-

derived hyperpolarizing factor, 
bradykinin, vasocontractile mediators: 
endothelin , angiotensin II. 

  Cytokines interact with VSMCs(vascular 
smooth muscle cells) to activate Ca2+, 
protein kinase C, Rho-Kinase, and MAPK 
pathways, which promote cell growth and 
migration, and VSM reactivity. Cytokines are 
either proinflammatory or inflammatory. 

 Proinflammatory cytokines: Produced by 
activated macrophages, mediate the 
following effects- Up regulation of 
inflammatory reaction by TNF-α, IL-1, IL-
6, IL-12, IL-19, and IFN-β.- Stimulation of 
acute phase reactants TNF-α, IL-1, IL-6, 
IL-11, IFN-γ, TGF-β.- Chemoattractant such 
as IL-8, MIP-1α (Macrophage Inflammatory 
Proteins) ,MIP-1β, RANTES(regulated on 
activation, normal T cell expressed and 
secreted) PF-4, MCP-1, -2, -3(monocyte 
chemoattractant protein) 

 Anti-inflammatory cytokines are involved 
in the down-regulation of inflammatory 
reactions. 

 
They include IL-4, IL-10, IL-13, IFN-α, and TGF-
β. (Transforming growth factor) The anti-
inflammation induced vascular injury results from 
interaction of the inflammatory cells, the 
endothelial cells(EC), vascular smooth muscle 
cells(vsmc) and extra-cellular matrix (ECM).  
 

 ECs are major determinant of vascular 
tone, leukocyte adhesion, and SMC 
proliferation. IL1activates T cells;IL-2, 
which stimulates proliferation of antigen-
activated T and B cells; IL-4, IL-5, and IL-6, 
which stimulate proliferation and 
differentiation of B cells;  

 IFNγ, which activates macrophages; and 
IL-3, IL-7 TNFα, IFN-γ, IL-8, and MCP-1 
influenced tissue factors which initiated 
coagulation cascade and down-regulated 
anticoagulant thrombomodulin. 

 TNF-α enhanced the endothelial cells to 
produce anti-fibrinolysis PAI-1 [32]. GM-
CSF, which stimulate haematopoiesis. 
Platelet derived growth factors were the 
main inducers of MCP-1 gene [33]. 

 The activated platelets stimulated NF-κB in 
endothelial cells and enhanced the 
expression of leukocyte receptors which 
induced the secretion of MCP-1 and IL-8. 
Besides, the significant increased 
expression of lung PAR-1 on pulmonary 
cells, as fibroblasts, macrophages, 
epithelial and endothelial cells might 



 
 
 
 

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241 

 

represent another cause for elevated 
MCP-1 (monocyte chemoattractant protein 
and IL-8 chemotaxis molecules [34]. 

 

Role of Endothelial cells: Under normal 
conditions, the endothelium maintains a 
vasodilator, antithrombotic and anti-inflammatory 
state. For vascular homeostasis, endothelial cells 
are of utmost importance and they produce a 
variety of mediators, surface proteins, and 
autocoids involved in vasomotion, coagulation, 
and inflammation [35]. Endothelium separates 
blood clotting factors from exposure to 
subendothelial prothrombotic extracellular matrix 
components. Endothelium also expresses 
vasoactive factors that modulate platelet 
reactivity, coagulation, fibrinolysis and vascular 
contractility, all of which contribute to thrombotic 
formation. Such factors include nitric oxide, 
prostacyclin, Von Willebrand factor (VWF), 
thrombomodulin, endothelin, etc. Endothelial 
cells counteract coagulation by providing tissue 
factor and thrombin inhibitors and receptors for 
protein C activation. 
 

Role of TNF alfa and C3: When TNF-α is 
upregulated, it contributes to changes in 
coagulation and C3 induction [36]. TNF-α plays a 
pivotal role in the disruption of macrovascular 
and microvascular circulation both in vivo and in 
vitro [37] and is an important cytokine that can 
induce both apoptosis and inflammation [38]. In 
the presence of ROS, there is an increased 
production of TNF-α and, in turn, TNF-α 
signalling accentuates oxidative stress [39]. TNF-
α up regulation is also associated with a changed 
coagulation propensity [40]. In short, TNF-α 
participates in vasodilatation and oedema 
formation, as well as leukocyte adhesion to the 
epithelium through expression of adhesion 
molecules. Furthermore, it regulates blood 
coagulation, contributes to oxidative stress at 
sites of inflammation, and indirectly induces fever 
[41]. TNF-α also plays a central role in the 
pathogenesis of insulin-resistant metabolic 
derangements. When TNF-α is upregulated, it 
contributes to changes in coagulation and C3 
induction. TNF-α plays a pivotal role in the 
disruption of macro vascular and microvascular 
circulation both in vivo and in vitro and is an 
important cytokine that can induce both 
apoptosis and inflammation. In the presence of 
ROS, there is an increased production of TNF-α 
and, in turn, TNF-α signalling accentuates 
oxidative stress. 
 

TNF-α upregulation is also associated with a 
changed coagulation propensity. In short, TNF-α 

participates in vasodilatation and oedema 
formation, as well as leukocyte adhesion to the 
epithelium through expression of adhesion 
molecules. Furthermore, it regulates blood 
coagulation, contributes to oxidative stress at 
sites of inflammation, and indirectly induces 
fever. TNF-α also plays a central role in the 
pathogenesis of insulin-resistant metabolic 
derangements. TNF can induce platelet 
consumption, and platelets do express TNFR1 
and TNFR2 [42,43]. TNFR1 expressed on other 
cells also causes the release of factors with 
agonist activity for platelets and TNF-α is able to 
activate platelets through stimulation of the 
arachidonic acid pathway. 
 
Complement c3: RBCs carry the complement 
receptor 1 (CR1), also known as C3b/C4b 
receptor or CD35, on its membrane [44]. Immune 
complexes, which have reacted with complement 
and bear C3b fragments also bind to the CR1 on 
human RBCs, and CR1 on RBCs serves as a 
transport system for immune complexes in the 
circulation to prevent immune complex 
deposition outside the fixed macrophage system 
[45,46]. Complement also interacts with the 
surface of activated platelets as well as with 
other components of the complement system 
including, C1q, C4, C3 and C9, which bind to 
activated platelets, [47]. Furthermore, thrombin-
activated platelets can actually initiate the 
complement cascade, [48] and C3a and its 
derivative C3a-des-Arg, induce platelet activation 
and aggregation in vitro [49]. Platelets express 
complement receptors C3aR, CR4, as well as a 
receptor for iC3b and C5a, and the C1q 
receptors gC1qR and cC1qR on their 
membranes. cC1qR, in particular, was shown to 
mediate platelet aggregating and activating 
effects. Of importance is that platelets may also 
interact with the complement system via   
proteins that are not considered classical 
complement receptors, such as P-selectin [50] or 
GP1bα [51]. 
 
TM-PS-EPCR SYSTEM: Marlies Van de 
WouwDésiré Collen and Edward M. Conway et al 
extensively reviewed this aspect [52] to                
which interested readers may refer for more 
details. 
 
Thrombin-mediates activation of protein C (PC), 
with Thrombomodulin (TM), acting as a co-
faactor. Thrombomodulin, a cell surface-
expressed glycoprotein, synthesized by vascular 
endothelial cells, is critical for PC activation y the 
thrombin–TM complex is further enhanced ≈20-



 
 
 
 

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242 

 

fold in vivo when PC is bound to the endothelial 
cell protein C receptor (EPCR). Platelet factor 4 
(PF4) accelerates PC activation by inducing a 
conformational change that increases its affinity 
for thrombin–TM complex .Activated PC (APC) is 
a known natural anticoagulant. APC and EPCR 
have a role not only in coagulation but also in 
inflammation also APC suppress further thrombin 
formation by proteolytic inactivation of the 
coagulation factorsVa and VIIIa. Along with 
protein S (PS), APC may also increase 
fibrinolytic activity, by neutralizing plasminogen 
activator inhibitor 1 (PAI-1). This results in a 
hypercoagulable state. Pro-inflammatory cellular 
effects of coagulation proteases as well as the 
anti-inflammatory effects of APC/EPCR are 
mediated by signalling via protease activated 
receptors PAR on mononuclear cells, endothelial 
cells, platelets, fibroblast, and smooth muscle 
cells. The beneficial effects of APC in sepsis are 
mainly dependent on the PAR-mediated cell-
protective properties rather than the 
anticoagulant protease function on coagulation 
cofactors FV/Va and FVIII/VIIIa. Protein C, which 
is activated by thrombin, complexes with 
endothelial protein C receptor and 
thrombomodulin and together with protein S 
forms the activated protein C complex that 
inactivates activated coagulation factors V and 
VIII. The receptor PAR-1 is differentially  
activated by thrombin and the activated protein 
C/EPCR complex, resulting in antithrombotic and 
anti-inflammatory effects. Thrombin and 
vasoactive agents release von Willebr and             
factor as ultra-large platelet-binding multimers, 
which are cleaved by ADAMTS13. Platelets              
can also facilitate leukocyte-endothelium 
interaction. Platelet activation is prevented by 
nitric oxide, prostacyclin and exonucleotidases. 
Thrombin-cleaved ADAMTS disintegration of 
platelet aggregates while tissue-type 
plasminogen activator initiates fibrinolysis.             
Fibrin and products of platelets and  
inflammatory cells modulate the angiogenic 
response of endothelial cells and contribute to 
tissue repair. 

 
Endothelial PARs (Protease activated 
receptors) participate in the regulation of 
vascular tone and permeability. In endothelial 
cells, PARs play a key role in promotion vascular 
barrier function as they provide a positive signals 
for endothelial adhesion molecules (vascular cell 
adhesion molecule-1 (VCAM-1), intercellular 
adhesion molecule-1(ICAM-1), and E-selectin 
[53]. PARs contribute to the pro-inflammatory 
response. For example PAR4 induces 

leukocyte migration and PAR2 helps 
macrophages to produce cytokines such as 
interleukin-8 (IL-8). Activation of PARs 
alternatively lead to the transactivation of and 
signalling through receptors such as co-
localized PARs, ion channels, and toll-like 
receptors. 
 
4.1.6 Role of other elements of innate 

immunity 
 
4.1.6.1 Role of the interferons 
 
Interferons(IFNs) are a group of signalling 
proteins made and released by host cells in 
response to the presence of several                   
viruses. Type I interferons (IFN-alpha and IFN-
beta) are secreted by virus-infected cells                 
while type II, immune or gamma interferon       
(IFN-gamma) is mainly secreted by           
components of both innate and adaptive 
immunity T cells (of adaptive immunity), 
natural killer (NK) cells and macrophages (of 
innate immunity). 
 
IFNγ, a cytokine which is crucial for innate and 
adaptive immunity against many pathogens is 
produced:  
 

1. As a part of the innate immune 
response: Natural killer (NK) Natural killer 
T (NKT) cells Mucosal epithelial cells, 
Macrophages Innate lymphoid cells(ILC) 
produce it . 

2. As a part of adaptive immunity: CD4 Th1 
cells, CD8 cytotoxic T lymphocyte (CTL) 
produce it. 

 
4.1.7 Functions it serves 
 

 Macrophage activation Increases their 
antigen presentation and lysosome    
activity. 

 Increased expression of class I and class II 
MHC molecules.  

 Increased expression of APCs (antigen-
presenting cells) through induction of 
antigen processing genes, including 
subunits of the immunoproteasome 
(MECL1, LMP2, LMP7), TAP and              
ERAAP and direct upregulation of          
MHC heavy chains and B2-microglobulin 
itself. 

 Role in macrophagepolymorphism: M1 
macrophages are stimulated by interferon 
(IFN)-γ which secrete proinflammatory 
cytokines (like TNF-α, IL-1β, IL-12, IL-18) 



 
 
 
 

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and the chemokines. (like CCL15, CCL20, 
CXCL8-11 and CXCL13). 

 Antiviral (replicatory), immuno-regulatory, 
and anti-tumour properties [19]. 

 Aberrant IFNγ expression causes number 
or autoimmune diseases. 

 Activates inducible nitric oxide synthase 
(iNOS). 

 Induces production of IgG2a and IgG3 
from activated plasma B cell. 

 Promotes adhesion and binding required 
for leukocyte migration. 

 Primes alveolar macrophages against 
secondary bacterial infections. 
 

How IFNγ exerts its Cellular responses? 
 

1. It interacts with interferon gamma receptor 
1 (IFNGR1) and Interferon gamma 
receptor 2(IFNGR2).  

2. Binding activates JAK-STAT pathway. 
3. IFNγ also binds to the glycosaminogly can 

heparan sulphate (HS) and inhibits its 
biological activity. 

4. Promotes NK cell activity. 
 
IFN-α has a general inflammatory action which 
skews the immune response towards a Th1 
profile, Which leads to induction of classically 
activated M1 macrophages.(see Macrophage 
polymorphism below) 
 
1. IFN α Functions 
 

1. IFN-α8 enhances the proliferation of 
human B cells, and activates NK cells. The 
subtypes α10 and α2, and α8, are the most 
efficient NK cell activators.  

2. Subtypes α21 and α2 enhance the 
expression of IFN-gamma inducible 
protein-10 (IP10),a chemokine, that 
promotes Th1 inflammatory response. in 
dendritic cells.  

3. IFN-α1 causes increased HLA-II 
expression and can directly inhibit tumour 
cell growth in vitro.  

4. Subtype α2 increases the expression of 
HLA-I molecules, which correlates with 
IFN-α-mediated activation of memory CD8 
cells and increased catalytic action against 
virally infected cells and tumour cells (via 
cytotoxic CD8 cells). 

 
Interferon beta: It is released at the end of an 
immune attack, blocks the action of gamma 
interferon and helps to reduce inflammation and 
the body's immune reaction. 

Role of other important innate cellular 
elements:  
 
These are presented in Appendix 4 
 

 Role of adoptive immunity in Covid lung 
pathology: 

 

CD8+ T cells and CD 4+ at cells: The autopsy 
findings considered above, showed that 
CD8+and CD4+ cells in the lung tissue 
interstetium. CD 8+ CD8+ T cells directly kill the 
virus upon stimulation. CD 4+ cells helps to 
secrete antibodies which have diverse actions. 
 

Ali Ganji et al. [53] have shown that CD8 MFI 
increased significantly in COVID-19 infected 
patients (P < 0.05), implying increased 
expression of CD 8+ T cells. 
 

Zheng et al. [54] found that the total numbers of 
T cells, NK cells and CTLs were reduced in all 
patients, with severe cases of Covid 19 having 
significantly lower proportions than those seen in 
mild cases. CD8+ T and NK cells from COVID-19 
patients had increased expression of the 
inhibitory receptor NKG2A. Furthermore, cells 
expressing NKG2A had diminished production of 
CD107a, IFN-γ, IL-2, TNF-α and granzyme B. 
These findings suggest functional exhaustion of 
NK and CD8+ T cells and inhibition of antiviral 
immunity during SARS-CoV-2 infection. It was 
opined that down regulation of NKG2A may be 
crucial for disease control.  
 

 Helper T cells: Type 1 helper (TH1), cells 
produce interleukin (IL)-2, gamma-
interferon (IFN-gamma) and tumour 
necrosis factor-beta, (pro-inflammatory). 
Th1 activate classically activated M1 
macrophages. Cells are cytotoxic and 
hence kill the virus laden cells, when 
activated. The zCD4+cells helps to 
stimulate B-cell function. 

 

Type 2 helper (TH2) cells express IL-4, IL-5, IL-6 
and IL-10 (anti-inflammatory). 
 

TH2 cells activate alternately activate M2 
macrophages.  
 

Role of complement in adaptive immunity: 
The classical complement pathway is activated 
by the virus in adaptive immune cells .It takes 
part in MAC induced cell lysis by itself. Also it 
acts through potentiation loop in producing 3Cb 
and classical 3C esterase. Its role in complement 
mediated phagocytosis and complement 
mediated cytotoxicity, as already seen above. 



 
 
 
 

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The central Role of Alveolar Macrophages 
(AM): 
 

 Under physiological conditions the 
expression of the phagocytic receptor 
Macrophage 1 antigen (Mac-1) keeps the 
AMs down-regulated, to prevent 
damage of body tissues from the 
activated AMs.  

 The adaptive immunity is suppressed 
through AM's effects on interstitial dendritic 
cells, B-cells and T-cells. 

 The macrophage performs the phagocytic 
function, both IgG mediated(through 
Fcy .receptor)and complement 
mediated,(through CR1,CR2 and CR3 
receptors) . 

 Can cause tissue damage through PR 
inflammatory cytokines (mediated by 
M1 macrophages) can exert anti 
inflammatory effect with anti-
inflammatory cytokines as well as 
healing of damaged tissues by fibrosis 
(through M2 type macrophages.)  

 Play role as antigen presentation cells 
(ARC) and recognizes PAMPs of the virus 
with the PRR,on its surface, in conjunction 
with MHC class 2 molecules . 

 It controls through, INOS(inducible nitric 
oxide synthase), the differentiation and 
maturation of dendritic cells through. 
Inhibition of the granulocyte-macrophage 
colony-stimulating factor (GM-CSF)and 
TNF-alpha-mediated mechanisms. 

 Through il 4 and iL10, it causes the 
reduced production of metallo-
proteinases (endopeptidases which break 
down collagen and other extracellular 
proteins) by human AMs. 

 Causes differentiation of naïve CD4-T cells 
into mature Th2 type cells. 

 Il4 enhances MHC class II antigen and 
Mac-1(surface receptor as part of innate 

complement system) expression, thus 
promoting phagocytosis. 

 Il10 inhibits the secretion of pro-
inflammatory cytokines TNF-alpha and 
INF-gamma, thus suppressing the 
proliferation of T-cells, NK cells, and 
AM. 

  By similar immunomodulation 
mechanisms to TGF-β. IL-10reduces the 
rate of apoptosis. Indirectly enhancing 
alveolar macrophage-mediated inhibition of 
T-cell proliferation. Alveolar macrophages 
induce expression of the αvβ6 integrins, 
the cell-surface receptors, activate TGF-β. 

 TGFβ tightly regulates anti-
inflammatory activity by suppressing pro-
inflammatory cytokine production, thereby 
inhibiting T-lymphocyte function. 

 This induces a downstream signalling 
cascade leading to transcription factors, 
regulating the expression of TGF-β target 
genes 

 Important inhibitor receptors of AMs 
include TIM-3, PD-1, CD32b, and 
CD200R. 

 
The pathways by which macrophages are 
activated and deactivated are shown in Table 1 
below. 

 
Macrophage polymorphism: The alveolar 
macrophages (AM) exist as two phenotypes, M1 
and M2 macrophages, which have different 
means of stimulation, express different kinds of 
cytokines and chemokines and have opposite 
physiological actions. The M1 macrophages are 
PR inflammatory and M2 are not only anti 
inflammatory in function, but also have action on 
extracellular matrix promoting healing by 
stimulating collagen fibres, leading to fibrosis. M2 
macrophages have 3, M2b and M2c. The salient 
points of both the phenotypes and the sub-types 
are shown in Table 3. 

 
Table 1. Activation of AM- sequence of events 

 

1. Binding of PAMPs to TLRs.(PRPs) 
2. Actin polymerization (in alveolar macrophages). 
3. Suppression of integrin expression 
4. Deactivation of TGF-β and the down regulation of the basal phosphorylation level of SMAD 2/3;  
5. Activation and detachment of alveolar macrophages from the alveolar epithelial cells  
6. Macrophages become primed (by IFN-γ and TNF-α) 
7. Phagocytosis and secretion of proinflammatory cytokines (TNF-α and IL-6) 
8. The ROS (reactive oxygen species) produced by respiratory burst. 
9. Oxidative damage to lung tissue. 
10. Positive feedback effect -Enhancement of production of TNF-α by macrophages (step 7). 



 
 
 
 

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Table 2. Deactivation of AMs - sequence of events 
  

1. Secretion of IFNγ by activated lymphocytes. 
2. Stimulation of the production of matrix metalloproteinase MMP-9 by macrophages. 
3. MMP-9 activates latent TGF-β. 
4. Reduced expression of αvβ6 integrins on alveolar epithelial cells. 
5. Return of the alveolar macrophage to a resting state 
* AMs have been reported to produce MMP-9 partly via PGE2-dependent PKA signaling pathways, which are the 

pathways involved in the inhibition of phagocytosis. 
**Activation of TGF-β is also advantageous because its production stimulates collagen synthesis in interstitial 

fibroblasts, which is necessary for restoring alveolar wall architecture. 
 

Table 3. Different polymorphic types of macrophage 
 

Type of 
macrophage 

 Stimulated by  Express  Functions  

M1 
macrophages 

 (Classically 
activated)  

1.LPS  

 

2. Th1 cytokines  

 (IFN-γ, IL-2, IL-12, IL-
18 and TNF-β)  

3.GM- CGO  

 

(TNF-) α, IL-1, IL-6, and  

IL-12, and type I  

interferons (IFN) Th1 
cell-attracting 
chemokines  

(CCL5 CXCL9 and  

CXCL10) ( (RANTES)  

 Pro-inflammatory 

M2  

Macrophages 
(alternatively 
activated 
macrophages 
(AAMs) 

1.Th2 cytokines 
including (IL-4, IL-5, 
IL-6, and IL-10)  

 

2. M-CSF 

 

1. Scavenging receptors  

2. Mannose and 
galactose receptors.  

3. Secrete high amount 
of IL-10  

4. Express higher levels 
of the IL-1 decoy 
receptor and IL-1RA  

5. Express the 
chemokines CCL17, 
CCL22 and CCL24  

1. Anti-inflammatory action  

2. Higher phagocytic activity  

3.Promotetissue remodelling,  

4.Vasculogenesis  

 

5. Tumour progression  

 

M2 a  

Macrophages 

 IL-4 and IL-13  1. Upregulate expression 
of Arginase-1, mannose 
receptor MRc1 (CD206),  

2. Antigen presentation 
by MHC II systemof IL-10 

and TGF- . 

Anti-inflammatory 

M2 b 

Macrophages 

immune complexes   

LPS  

IL-1, IL-6, IL-10, TNF-   Anti-inflammatory 

 M2 c  

Macrophages  

IL-10,   

Transforming growth  

factor beta (TGF- ) 
and glucocorticoids,  

IL-10 and TGFβ Suppression of inflammatory 
response 

 

5. SUMMARY 
 

The elusive pathology of COVID 19 lung disease 
is dueto its protean and varied manifestations. 
Thus It might resemble from consolidation 
/pulmonary oedema/ ARDS or cytokinestorm 
;yetit is distinct from each of these specific 
syndromes. In fact COVID lung pathology 
resemblesa mixture of all theseindividual 

entities.Alveolitis due to inflammatory cytokines 
explains the consolidation finding. Damage to 
capillaries with consequent seepage of translate 
explains the pulmonary oedema like component. 
This in combination with interstitial fibrosis 
formed due to M2 macrophage 2, with resultant 
hypoxia might explain the ARDS-like picture. The 
terminal events of disseminated intravascular 
coagulation (DIC) and multi organ dysfunction 



 
 
 
 

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(MOD), which is a common pathway for severe 
sepsis or cytokine storm like picture seen in a 
few COVID 19 patients which contributed to the 
overall mortality due to COVID 19.The failure to 
pin point to single pathology, perhaps is due to 
this fact. Further the simultaneous occurrence of 
thrombotic and haemorrhage, seen in COVID 
lung, suggests a range of diseases such as 
activation of simple coagulation cascadeand 
subsequent fibrinolysis, small vessel 
vasculitis to thrombotic thrombocytopenia. 
Simple coagulation cascade activation/ 
fibrinolysis, cannot explain either the presence of 
immune cells like CD8+ and CD4+ cells nor the 
consolidation/fibrosis component. Small vessel 
vasculitis(capillaritis) / luecocytoclastic / 
hypersensitive angiitis is a systemic disease 
and the specific histological features like 
leukocyteclasia (a process in which the 
neutrophils are destroyed leading to debris 
collection) is not demonstrated, in the autopsy 
findings of COVID 19. Further it is either due to 
drug induced allergy or idiopathic. 
Thethhrombotic phenomena are not a feature of 
small vessel vasculitis. The acute nature and non 
involvement of medium sized blood vessels and 
absent fibroid necrosis are points 
Wagnersgranulomatosis a non possibility. 
The absence of haemoptysis even though, 
patchyhaemorrhages are seen on gross as well 
as microscopic autopsy findings indicates that 
the bleeding is not substantially enough to give 
rise to clinically haemoptysis which distinguishes 
COVID lung disease from Good.  
 
Pasture's syndrome the haemorrhagic part is 
perhaps due to purpura as supported by low 
platelet counts and presence of atypical 
megakaryocytes seen in the autopsy findings. 
This takes us to the possibility of thrombotic 
thrombocytopenia or coagulative 
microangiopathy which is a systemic 
syndrome unlike the localised pathology as 
seen in COVID 19. However all coagulative 
microangiopathy is described in literature in case 
of fall bladder, but not in case of Lung. If it is true, 
COVID 19 is the first ever disease to cause such 
"localised coagulative microangiopathy. 
Disseminated intravascular coagulation is a 
serious condition that may explain both the 
observed pathological entities, but its protean 
manifestation are not discernible in routine cases 
except the seriously terminally ill patients 
distained for MOD(multiorgan dysfunction). The 
elusiveness of COVID 19 lung pathogenesis 
could be due the culmination of more than one 
pathogenic pathway. The different pathways 

explaining the interstitial fibrosis and vascular 
changes already seen bear testimony to this fact. 
While the effector cells (macrophages, and other 
phagocytes, Nkcells, NAK cells and dendritic 
cells etc)do deliver the final blow, nevertheless 
the role played by other elements of both innate 
as well as acquired immunity(like antibody 
classes, opsonins and complement etc) cannot 
be ignored. It must be emphasized that immunity, 
innate or acquired can be no less damaging  
than the protection they offer against the 
invading pathogens. The system has inbuilt 
checks and controls, so that the destructive 
machinery is not directed against the healthy 
host cells, but are specifically directed against 
the pathogen or pathogen infected cell.The 
ingenuity of the pathogen to sabotage these 
inbuilt safeguards in immune system to farthen 
its interests, in which process, the fallout of 
deranged defence mechanisms, trains its guns 
against host's own tissues, as already discussed 
above. Thus, foundation for immune mediated 
injury, in COVID 19 induced lung damage is laid 
on a firm footing. 
 

6. CONCLUSION 
 
An integrated approach, taking into 
consideration, all the available clinical, 
laboratory, radiological and autopsy data lead to 
arriving at a possible mechanism underlying the 
lung damage in COVID 19.The pathway of 
complement activation, contact cascade, the role 
of the cytokines and the role of various elements 
of the innate and adaptive immunity are 
reviewed. The central role played by the 
macrophage polymorphism, in the pathogenesis 
and pathology of the COVID19 is stressed. The 
relevance of ARDS cytokine storm, the small 
vessel vasculitis, coagulative microangiopathy, 
disseminated intravascular coagulation and multi 
organ disfunction in relation to COVID 19 
pathology are discussed. It is also shown that no 
single mechanism could explain the whole gamut 
of the pathology and pathogenesis of COVID 19 
lung damage. The immune mediated damage 
seems to be more relevant ,rather than the 
infectivity of the virus. It is obvious that no single 
entity could explain the inflamatory,fibrotic and 
vascular features observed in the lung of COVID 
19 patients, it seems to be due to a mixture of 
different overlapping immune mechanisms, 
resulting in evolution of the unique pathogenic 
mechanism of COVID 19. It is perhaps justifiable, 
from the author’s point of view to call the COVID 
19 related lung damage as “Acute immune 
mediated Lung injury (AILI). 



 
 
 
 

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247 

 

CONSENT 
 
It is not applicable. 
 

ETHICAL APPROVAL 
 
It is not applicable. 

 
COMPETING INTERESTS 
 
Author has declared that no competing interests 
exist. 
 

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APPENDIX 1 MICROBIAL PATTERN RECOGNITION PROTEINS 
---------------------------------------------------------------------- 
1. Mannose receptor. 
2. complement receptors. 
3. DC-SIGN.  
4.Toll-like receptors(TLRs). 
5. Scavenger receptors CD14, and Mac-1 
 
The PRRs are divided into four families: 
 
1. Toll-like receptors (TLR) 
2. Nucleotide-binding oligomerization domain-like receptors (NLR) 
3. RIG-1 like receptors (RLR)- 
4. C-type lectin receptors (CLR) 
 
PAMPs 
 
1. Glycans 
 
Lipoglycans such as lipopolysaccharide, a component of the gram- bacteria outer membrane 
Peptidoglycans such as bacterial muramyl dipeptide 
 
b-1,3-glucans from the cell wall of various fungi species 
 
2. Proteins 
 
bacteria flagellin 
--------------------------------------------------------------------------- 
 

APPENDIX 2 
 
Interaction of PRRs and PAMPs: 
 
Step 1.  
 
Ligand recognition/ binding: 
PAMPs are recognized and are attached to PRRs. 
 
Step 2. Activation of the kinases and antiviral signalling cascades: 
 
1. TBK1 
 
(TANK-binding kinase 1) 2. MAPK 
(Mitogen-activated protein kinases)  
3. IKKα and IKKβ.  
κB kinase α and β 
 
Step 3. 
 
these kinases phosphorylate and activate  
interferon(IFN)-regulatory factors 3 and 7 (IRF3/7), AP-1, NF-κB, 
 Step 4.These proteins transcriptionally induce the gene expression of 
 1.type-I IFNs (mainly IFN-α subtypes and IFN-β),  
 
 
 
 



 
 
 
 

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Appendix 3. Laboratory tests reported in COVID 19. Their significance 
 

Laboratory test  Significance  

Increased  
ESR  
CRP (C-reactive protein) 
Ferritin  

 
Ac. phase reactants/markers of ac inflammation 
 

LDH. (lactic dehydrogenase) 
AST(Aspartate transaminase) 
Fibrinogen 
Prothrombin 

Liver cell dysfunction 

hs-cTnT(high sensitivity cardiac troponin ) Maker of cardiocyte damage. Ac MI, myocarditis 
PT(Prothrombine time) 
(both indicate clotting disorder causing 
bleed) 

Extrinsic coagulation pathway involvement. 

BU/BUN (blood urea nitrogen) 
Creatinine 

Renal function impairment. 
 

T8+/T4+ cells Immune reaction. 
Leucopenia /Lymphopenia 
Thrombocytopenia  
Neutrophilia 
Leucoerythroblasticpicture.  

Bone marrow insult 
Purpura 
Secondary infection or complication 
Bone marrow involvement in COVID 19. 

 

Appendix 4 
 
Role of other important innate cellular elements  
 
1. Natural killer cells: 
 
They are the counterparts of cells of adaptive immunity. 
Functions: They can directly kill the pathogen or through the antibody mediated cell mediated 
cytotoxicity. 
 
NK cell dependent antibody induced cytotoxicity:  
 

1. NK cell expresses Fcγ receptors - CD16 or FcγRIII. 
2. These receptors recognize and bind to the reciprocal portion of antibody, (such as IgG,) which 

binds to the surface of a pathogen-infected target cell.  
3. The NK cell releases cytotoxic factors that cause the death of the target cell through perforin - 

granzyme pathway. 
 
2. MAIT cells (Mucosal associated invariant T cells)  
 
A subset of T cells they display innate, effector-like qualities. AIT cells secrete pro-inflammatory 
cytokines and alsolyse bacterially-infected cells. Supports the adaptive immune response . They have 
memory like phenotype. 
 
3. Natural killer T (NKT) cells 
 
 A group of T cells that share properties of both T cells and natural killer cells.  
 
. Recognize foreign lipids and glycolipid antigens. 
 
4. Gammadelta T cells (γδ T cells) Subset of T cells -express a unique T-cell receptor (TCR)  
 
-initiation and propagation of immune responses 
 



 
 
 
 

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5. Innate lymphoid cells (ILCs)  
 
1. LCs contribute to immunity via 
a. secretion of signalling molecules, b. regulation of both innate and adaptive immune cells 
2) mucus production in the respiratory tract.  
3) Restoration and maintenance of epithelial integrity.  
4) secrete IFN-γ in response to viral infection in the lungs .  
 
6. Dendritic cells: 
 
These are professional antigen processing cells. Present antigens to T cells. 
 MHC class II molecules thereby are critical for the initiation of the antigen-specific immune 
response.2.  
 
Role of Nab (natural antibodies) 
 

1. Opsonisation 
2. Activation of the Complement. 

 
MHC class II molecules: The main function of major histocompatibility complex (MHC) class II 
molecules is to present processed antigens, which are derived primarily from exogenous sources, to 
CD4(+)Tlymphocytes. 
_________________________________________________________________________________ 
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provided the original work is properly cited. 

 
 

 
 

 

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