key: cord-288017-f9b3t0ts
authors: Kabeerdoss, Jayakanthan; Danda, Debashish
title: Understanding immunopathological fallout of human coronavirus infections including COVID‐19: Will they cross the path of rheumatologists?
date: 2020-08-10
journal: Int J Rheum Dis
DOI: 10.1111/1756-185x.13909
sha: 
doc_id: 288017
cord_uid: f9b3t0ts

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection causing coronavirus disease 2019 (COVID‐19) is the biggest pandemic of our lifetime to date. No effective treatment is yet in sight for this catastrophic illness. Several antiviral agents and vaccines are in clinical trials, and drug repurposings as immediate and alternative choices are also under consideration. Immunomodulatory agents like hydroxychloroquine (HCQ) as well as biological disease‐modifying anti‐rheumatic drugs (bDMARDs) such as tocilizumab and anakinra received worldwide attention for treatment of critical patients with COVID‐19. This is of interest to rheumatologists, who are well versed with rational use of these agents. This brief review addresses the understandings of some of the common immunopathogenetic mechanisms in the context of autoimmune rheumatic diseases like systemic lupus erythematosus (SLE) and COVID‐19. Apart from demographic comparisons, the role of type I interferons (IFN), presence of antiphospholipid antibodies and finally mechanism of action of HCQ in both the scenarios are discussed here. High risks for fatal disease in COVID‐19 include older age, metabolic syndrome, male gender, and individuals who develop delayed type I IFN response. HCQ acts by different mechanisms including prevention of cellular entry of SARS‐CoV‐2 and inhibition of type I IFN signaling. Recent controversies regarding efficacy of HCQ in management of COVID‐19 warrant more studies in that direction. Autoantibodies were also reported in severe acute respiratory syndrome (SARS) as well as in COVID‐19. Rheumatologists need to wait and see whether SARS‐CoV‐2 infection triggers development of autoimmunity in patients with COVID‐19 infection in the long run.

There are demographic, immunological and therapeutic similarities and dissimilarities between HCoV infections and autoimmunity.

In general, adult women have stronger immune response and they are protected more often from infectious disease compared to men of similar age. 3 Women appears to have robust antimicrobial immune responses, especially against viral infections. X chromosomes and sex hormones are thought to be responsible for this phenomenon. In addition, negative regulators of immune response are less marked in woman as compared to men, for example lower number of circulating T-regulatory cells and lower expression of immune checkpoint inhibitors like PD-L1 in T-cells of women. 3 Coronavirus strains SARS-CoV and SARS-CoV-2 utilize angiotensin I converting enzyme (ACE) 2 as a receptor for entry into host cells. 4 ACE2 is differentially expressed in different organs; high levels are reported in the small intestine, colon, heart, muscle, kidney, testis and moderate levels in lungs. Expression of ACE2 is also higher in males compared to females, especially in liver and lung tissues even though its gene is present in the X chromosome. 5 ACE2 activity and expression is regulated by 17β-estradiol. 6 Messenger RNA (mRNA) expression of ACE2 correlates with immune signatures in lungs and it is dependent upon age and gender.

There is positive correlation between ACE2 expression and immune signatures in the lungs of men and older individuals, whereas negative correlation is observed in women and younger individuals. 7 This might be the reason for excessive immune response in the form of the cytokine storm observed in older-aged males that results in severe respiratory complications. However, SARS-CoV-2 infects both genders equally, although higher mortality is observed in males. 8, 9 In an animal model studies, males were found to be highly susceptible to SARS-CoV infection and more severe lung pathology.

Mortality of male mice was higher than that of female mice and it was dependent on viral load. Blocking estrogen receptor signaling, however, led to an increase in mortality even among SARS-CoV in- Similar to animal studies, male population is predominantly susceptible to SARS-CoV-2 infection and accounts for nearly 60% of all cases of COVID-19 with higher mortality. 11 Similar gender bias was also observed in MERS-CoV infection, although it was attributed to social activities and religious customs that involved more men than women in the Middle East.

African American women are at 4 times higher risk and Latino American as well as Asian women are at 2 times higher risk for developing SLE than European American women. SLE disease severity, number of clinical manifestations, prevalence of autoantibodies and nephritis as well as mortality are higher in African American, Asian and Hispanic populations as compared to the White populations.

However, socio-economic and environmental background may also be confounding factors that influence ethnicity-based prevalence and phenotypic differences in SLE. 12 As on 16 June 2020, mortality rate (deaths/ total cases) of COVID-19 infection in Europe, North America, Asia and Africa are 8.2%, 5.8%, 2.5% and 2.7% respectively. 13 However, mortality rate of COVID19 in the USA is disproportionately higher among Blacks (92.3 deaths per 100 000 population) and

Hispanics/Latino Americans (74.3 deaths per 100 000 population) than the White American population (45.2 deaths per 100 000). 14, 15 Blacks, Asians and minority ethnic (BAME) groups are also found Ethnicity also influences type I IFN secretion, as Asians and African Americans have higher type I IFN expression in peripheral blood cells as compared to Caucasians. 19, 20 This observation goes hand in hand with prevalence of lupus in these ethnicities, a predominantly type 1 IFN-driven disease.

Type I IFN expression is also lower in male individuals compared to females, again keeping in line with high female predominance in lupus.

Body mass index (BMI) and smoking also increases type I IFN expression and inflammatory cytokines. 20 These 2 risk factors tend to adversely affect outcome of COVID-19 disease as well as lupus and other systemic autoimmune diseases. [21] [22] [23] These reports suggest that gender, ethnicity, BMI and smoking affect type I IFN secretion. Hence, male gender, African ancestry, high BMI and smoking are risk factors for severe or critical COVID-19 disease 21 ; interestingly, these are also risk factors for severe lupus. This mechanism of type I IFN induction is strikingly similar to that of SLE. Early secretion of type I IFN by pDCs is important for controlling viral replication and preventing dissemination of virus to major organs. Depletion of pDCs results in loss of antiviral type I IFN response and impaired survival of virus-specific natural killer (NK) or CD8+ T-cells. 29 Numbers of pDCs gradually decrease as age increases, whereas there is no change in conventional DC (cDC) cells. 30 This may be the reason for reduced antiviral IFN responses in older age and increased mortality among the elderly due to COVID-19.

There is nearly 8-fold higher secretion of type I IFN by pDCs upon recognition of MERS-CoV compared to that of SARS-CoV. 31 This may be one of the factors contributing to the higher mortality rate observed in MERS than SARS and COVID-19.

Type III IFN (IFN-λ) secretion is also higher by coronavirus-infected pDC and its levels were similar to that of type I IFN. Signal In summary, both HCoV-mediated diseases and SLE have robust production of type I IFN. In both conditions, pDC is a major cellular source for type I IFN via TLR7 and cGAS-STING signaling, as well as via the TLR3 pathway, a relatively lesser known mechanism.

Early response to SARS-CoV-2 infection is mediated by CD8 cells.

Dramatic reduction in the number of CD4 and CD8 T-cells during the acute phase of infection in patients of SARS and COVID-19 are uniformly reported. Decrease in activated CD8 T cells and increase in antibody-

during convalescence phase of COVID-19 are other encountered observations. 36 Low levels of T-cells (CD3+), both CD4 + T-cells and CD8 + T-cells, are also associated with severity and hospital death in COVID-19. 8, 9, 37 Neutrophil to lymphocyte ratio as a predictor for severity in COVID-19 has also been studied. 11 Type I IFN is required for activation of CD4 Th1 cells that sustain antiviral response of CD8 CTLs. In parallel, type I IFN is also required for differentiation of TFH cells that mediate B cell differentiation and antibody production. 45 Therefore, type 1 IFN are crucial for immediate and long-term protection against COVID-19.

Wide variability in cytokine secretion patterns that is noticed among patients with SARS and COVID-19 determines the course of disease.

Pre-existing comorbidities of these patients also synergistically alter cytokine levels and decide outcome. ARDS, disseminated intravascular coagulation and multiple-organ failure rapidly progress in severe COVID-19 patients, leading to death within 7 to 14 days of intensive care unit admission. Increased infiltration of neutrophils and macrophages as well as secretion of high levels of pro-inflammatory cytokines result in a condition called cytokine storm. 46 Cytokine storm could be the leading cause for respiratory complications and multi-organ failure in patients with COVID-19.

Reduced lymphocytes, increased cytokine levels and abnormal coagulation parameters are frequent in these cases. Reduced IFN levels and increased viral load are higher in critical and severe cases as compared to mild to moderate patients with COVID-19. 47 In view of diminished lymphocyte and dendritic cell function, neutrophils and macrophages take over antiviral defense response. 47 Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) are major pro-inflammatory cytokines secreted by these cells that induce tissue damage, eventually leading to alveolar flooding and fibrosis. 48 Cytokine storm is also a relatively common complication in pa- 

Age-dependent altered innate immune response to HCoV was studied in a mice model. Young mice infected with SARS-CoV efficiently cleared the virus. In contrast, aged mice showed exacerbated immune response to virus with increased lymphocyte infiltration in lungs. During initial infection in young mice, activation of innate immune cells, namely pDC, macrophages and NK cells were involved in viral clearance. However, this response was not effective in aged mice to contain the virus; instead, a robust cytokine storm and altered lung pathology followed the immunological war against the virus in older mice. 54 In a macaque model of SARS-CoV infection too, aged macaques had more severe lung pathology, lower expression of type I IFN and higher expression of pro-inflammatory cytokines as compared to younger macaques. 55 As mentioned earlier, SARS-CoV2 infects hosts equally across all age groups, but complications and fatality are noted much more commonly in older populations.

Early type I IFN response is important for preventing HCoV-mediated inflammation and severe disease. 27 Both IFN secretion from innate cells like pDC and response threshold by its receptor in T-cells are impaired in older age as compared to young individuals. 18, 29, 30 Delayed IFN response causes apoptosis of T-cells and recruitment of monocytes and neutrophils, leading to cytokine storm and lung injury. 26, 48 Inflammation in the form of chronic subclinical systemic inflammation and immune senescence, that is reflected by blunted and impaired immune response, are other factors contributing to age-related differential COVID-19 pathogenesis. 56 On the other hand, SARS-CoV-2-associated multisystem inflamma- Kawasaki-like diseases have also been reported in some immunodeficiency states. 60 It is likely that children with MIS-C may have some underlying immunodeficiency state that is triggered into an auto-inflammatory syndrome by COVID-19 infection; only future studies can reveal exact immunological mechanisms behind this unique mimic of KD. 

During recent times, HCQ has been subjected to huge discussions in relation to its benefit and harm in COVID-19; its role in autoimmune diseases like rheumatoid arthritis (RA) and lupus are already established.

Antimalarial agents, chloroquine (CQ) and HCQ are drugs of choice for various connective tissue diseases. Both are immunomodulatory agents; unlike immunosuppressants, these drugs are safer for patients with chronic diseases. Role and mechanism of HCQ in management of autoimmune rheumatic diseases is discussed in a recent review. 68 Here we discuss its perspectives in COVID-19 ( Figure 2 ). CQ and HCQ not only interfere with TLR7/8-mediated signaling, there is evidence that it has an effect on TLR3 also. CQ inhibit IFN-β secretion and phosphorylation of STAT1 in human mesangial cells treated with TLR3 agonist polyinosinic-polycytidylic acid (poly I:C). 69 This may be one more effective mechanism of CQ and HCQ in treatment of lupus nephritis patients. As mentioned above, TLR3 also recognize SARS-CoV dsRNA and activates transcription factors 

In a small randomized controlled trial, treatment with HCQ was associated with reduced viral load and improvement in radiological progression on computed tomography images in patients with COVID-19. 76 However, another clinical study involving 11 patients showed failure of HCQ to clear viral load and no clinical benefit. 77 In an observational study, administration of HCQ in severe COVID-19 patients has shown no benefit in preventing intubation or death. 78 In other randomized and clinical observational studies, HCQ was not shown to be beneficial for patients who are transferred to the intensive care unit. 79 These studies were different in terms of dose of medication, day of starting treatment, primary endpoint and selection bias of severity (Table S1 ). Therefore, randomized clinical trials with larger sample size is warranted for testing its efficacy.

On the other hand, HCQ has been recommended as prophylactic regimen specifically for healthcare workers in India. 80 to patients with COVID-19 that it is a mild immunomodulatory F I G U R E 2 Hydroxychloroquine (HCQ) inhibits SARS-CoV-2 entry and inhibits virus-induced type I interferon (IFN) signaling and proinflammatory cytokines production. Here are the various pathways: 1. Angiotensin I converting enzyme 2 (ACE2) is an inducible gene. HCQ inhibit type I IFN, thereby inhibit ACE expression. Also HCQ may inhibit n-terminal glycosylation of ACE2. 2. HCQ can also inhibit viral entry by disrupting endosomal acidification. 3. HCQ alters endosomal pH, there by disrupts ligand binding to Toll-like receptor 3 (TLR3) and TLR7. 4. HCQ inhibit cGAS-STING (stimulator of interferon genes) signal and thereby reduce type I IFN and pro-inflammatory cytokines expression agent and not an immunosuppressant. While its use in hospitalized COVID-19 patients are not yet proven to be beneficial, several developing nations are using it in early disease and as a pre-exposure prophylaxis for frontline healthcare workers exposed to SARS-CoV-2, as recommended by Indian Council of Medical Research (ICMR) 80 (Table S1 ).

Presumable viral etiologies have been known for many connective tissue diseases. We might very well expect SARS-CoV-2 triggered development of autoantibodies. Some available evidence to support this notion are discussed in the following paragraphs. Injection of convalescent sera from SARS patients to rhesus macaques also causes lung injury with similar histopathological features as in human disease. 85 Thus convalescent sera containing autoantibodies or other antiviral antibodies might cross-react with antigens expressed in the lung. This has to be kept in mind while recommending over enthusiastic use of convalescent sera/plasma therapy in critically ill covid 19 cases.

High titers of anticardiolipin antibodies are also seen in SARS patients presenting with osteonecrosis. 86 In vitro experiments also reveal that sera of SARS patients contain autoantibodies targeting pulmonary epithelial cells and endothelial cells. 87 Another in vitro experimental study demonstrated anti-S2 spike antibodies in sera of SARS patients that can bind to epithelial cells inducing cytotoxic injury. 88 Sera from patients with autoimmune diseases like mixed connective tissue disease, and RA were found to have higher positivity for anti-SARS-CoV IgG and IgM as compared to healthy controls. 89 False positivity was also reported for anti-SARS-CoV antibodies in patients with SLE. 90 Cross-reactivity between anti-SARS-CoV antibodies and autoantibodies targeting the same antigenic target is possible. However, autoantibodies in SARS specifically bind to antigens expressed in lung tissue, and are not expected against cell nuclei (like ANA), against smooth muscles (like SMA) or against parietal cells (like PCA). 91 These studies show that both SARS-CoV and SARS-CoV-2 infections might induce expression of ANA and aPL antibodies. 84 Further studies are needed to delineate the spectrum and pattern of developing autoantibodies in patients with COVID-19.

Systemic vasculitis was noted in an autopsy study from 3 patients who died from SARS. 92 Simultaneous diagnosis of COVID- 19 and KD was also made in a 6-month-old child. 93 Outbreak of Kawasaki-like diseases is reported in 10 children, 8 of them were positive for either SARS-CoV-2 by nasal swab or antibodies. 57 Pediatric patients who were positive for SARS-CoV-2 IgG also developed cutaneous vasculitis lesions. 94 Development of cutaneous small vessel vasculits was seen in elderly female COVID-19 patients also on the 7th day after onset of symptoms. 95 SARS-CoV-2 infects endothelial cells and induces apoptosis as well as pyroptosis resulting in multi-organ dysfunction. 96 These show HCoV not only targets lungs, but can infect blood vessels, thereby causing multi-organ damage.

In summary, ANA and aPL autoantibodies can be seen in patients with SARS and COVID-19. Theoretically, these patients may have higher chances to develop autoimmune diseases in future, like APS or a lupus spectrum disorder. Rheumatologists will have to wait for the post-COVID-19 era to witness any unfolding of events towards a rising prevalence of lupus, vasculitic process or APS.

Complications and fallouts of COVID-19 disease have some similarities as well as dissimilarities with autoimmune diseases like SLE. While male gender, older age and people with metabolic syndrome seem to be at a higher risk of contracting more severe SARS-CoV-2 infection, younger females of African and Asian ancestry have higher risk for developing SLE; male gender among lupus patients, however, is an independent risk factor for severe disease. 

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