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*Corresponding author: E-mail: ibrahimshnawa3@gmail.com; 
 
Cite as: SHNAWA, IBRAHIM M S. 2025. “An Alum Loaded Macrophage Driven Autoimmune Myopathy”. Asian Journal of 
Immunology 8 (1):97-103. https://doi.org/10.9734/aji/2025/v8i1164. 
 
 

 
 

Asian Journal of Immunology 
 
Volume 8, Issue 1, Page 97-103, 2025; Article no.AJI.134974 
 

 
 

 

 

An Alum Loaded Macrophage Driven 
Autoimmune Myopathy 

 
IBRAHIM M S SHNAWA a,b* 

 
a Department of Medical Biotechnology, College of Biotechnology, AL-Qasim Green University, 

Qasim, Babylon, Iraq. 
b College of Nursing, University of Hilla, Babylon, Iraq. 

 
Author’s contribution  

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

 
Article Information 

 
DOI: https://doi.org/10.9734/aji/2025/v8i1164 

 
Open Peer Review History: 

This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers,  
peer review comments, different versions of the manuscript, comments of the editors, etc are available here: 

https://pr.sdiarticle5.com/review-history/134974 

 
 

Received: 25/02/2025 
Published: 03/05/2025 

 
 

ABSTRACT 
 

Immune mediated diseases and syndromes are rare and attributed at most to genetic and 
environmental interactions. Macrophagic Myofasciitis MMF is one of these syndromes sub-entities. 
In the present opinion the immunobiology of MMF was being reviewed. The molecular autoimmune 
mechanisms can be as follows; concurrent release of alum nano-molecules are taken up by 
macrophage persist in, combine with cellular proteins forming metalloprotein. It is now modified 
cellular protein in a modified macrophage which have DC marker, but still of macrophage 
morphology. Metalloprotein, when being extracellular on cellular burst or on diffusion to 
extracellular space will reach immune cells, in presence of; chronic induction, pathogenic allele, the 
HLA DR1 01 and the affected tissue microenvironment. Molecular mimicry, antigen bystander 
and/or epitope spreading response may operate and autoimmune tissue changes happened within 
continuum of granulomatous lesion developed in skeletal muscle at the injection site. Modified 
macrophage may migrate to regional lymph node and spleen the finally reach the brain. As a result, 
disturbance occurs in skeletal muscle functions and in brain cognition function. 

Opinion Article 

https://doi.org/10.9734/aji/2025/v8i1164
https://pr.sdiarticle5.com/review-history/134974


 
 
 
 

Shnawa; Asian J. Immunol., vol. 8, no. 1, pp. 97-103, 2025; Article no.AJI.134974 
 
 

 
98 

 

Keywords: Alum; allele; autoimmune; environment; genetics; granuloma; HLA; macrophage 
myopathy. 

 

1. INTRODUCTION 
 
Immuno-prophylactants are vaccines and sero-
therpeutics. These standard biologics are helpful 
for prevention and therapy, both in man and 
animals. Vaccines and adjuvants so far they are 
helpful but they are associated with an adverse 
effects. Vaccine and adjuvant adverse effects 
can be ramified into; vaccine and adjuvant 
associated disease enhancement VADE and 
vaccine failure VF (Shnawa, 2017, 2023, 
Shnawa & ALKhafaji 2023). One of the known 
VADE is Shoenfeld syndrome SS (Shoenfeld et 

al., 2011). SS grouped five disease sub-entities 
as; i- Postvaccination with adjuvanated vaccine 
illness, ii-Macrophagic myofasciitis illness MMF, 
iii – sick building illness, iv-Gulf war illness and v 
- siliconosis. This syndrome sub-entity is a 
molecular immunogenetic disease with 
presentation of an autoimmune reactions.              
It is an inducive chronic rare syndrome 
associated with specific human leukocyte  
antigen haplotype (Calarelli et al., 2024). The 
objective of the present opinion paper               
was to tackle the immunobiology [Box one] of 
MMF. 

 

BOX-One: Relevant Terminology (Abbas et al., 2015) 
1. Anergy: A state of unresponsiveness to antigenic stimulation. Lymphocyte anergy is failure of T 
and/or B cell clones to react antigen and is a mechanism of maintaining immune tolerance to self 
antigens. 
2. Antigen By- stander: Continued immune responses to infection modified proteins, an attendant 
inflammation allow exposure of autoantigens to immune responses. Theoretically, this could operate 
through T cell recognition resulting in help of potentially, B lymphocyte. 
3. Clonal ignorance: A form of lymphocyte unresponsiveness in which self antigens are ignored by 
the immune system even though lymphocyte specific for their antigens remain viable and functional. 
4. Clonal deletion: A mechanism of lymphocyte tolerance in which an immature T cell in the 
thymus or immature B cells in bone marrow undergoes apoptotic death as a consquences of 
recognizing self antigens. 
5. Epitope spreading: In autoimmunity it is found that the development of immune responses to 
multiple epitopes as an autoimmune disease originally target one epitope progresses, likely caused 
by further breakdown in tolerance and release of additional tissue antigen due to self protein 
stimulated by the initial response. 
6. Molecular Mimicry: A postulated mechanism of autoimmunity triggered by infection with a 
microbe that cross react with self antigen. Immune response to the microbe results in reactions with 
self tissue antigen. 
7. Sequestrated Antigens: There are certain tissue niches in which their specific antigens are not 
recognized to immune system cells during the ontogeny of the individuals. Like, eye vetrus fluid, 
semen plasm, and synovial fluid when exposed to immune cells will be recognized as foreign. 
8. Tolerance: unresponsiveness of adaptive immune system to antigen, as a result of inactivation 
or death of the antigen specific lymphocyte induced by the exposure to antigen. 

 

2. MACROPHAGIC MYOFASCIITIS MMF CONCEPT 
 
MMF is an uncommon immune mediated inflammatory disorder of muscle and is believed to be due to 
an alum in a vaccine combination exhibited persistence at the site of injection. The conditions 
characterized by diffuse myalgia, arthralgia and fatigue (Ravindran 2024, Dittmann 2000, Ieraeli et al  
2011). It is a rare inflammatory condition that affect skeletal muscle and connective tissue 
characterized by infiltration of macrophages into muscle tissue, in which the affected subject presents 
local or systemic manifestation. The local manifestation can be an immune active lesion of granuloma, 
in a rare muscle disease characterized by; microscopic lesions found in muscle biopsies that showed 
infiltration of the muscle tissue by PAS positive macrophages in light microscope and alum crystal 
inclusion in electron microscopic studies and they are traced in epimysium, perimysium, prefascular 
endomysium with crystal lesion composed of aluminum salt (Tervaert et al, 2023, Gibson, 2024). 
Hence, aluminum containing vaccines have been implicated. MMF lesions result from aluminum 
hydroxide adjuvant hidden within the tissue with frequent steady state release of alum causing 
immune reactions (Watad et al., 2017, Santos et al 2018, Caldarelli et al., 2024). 



 
 
 
 

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3. TIMELINE 
 
Knowing the past will in light the present and pin point directions to the future. So, the MMF timeline 
made in Table 1. 
 

Table 1. Macrophagic Myofasciitis timeline 
 

Achievement  Date  Reference  

MMF was initially described as an emergency entity by Franch 
myo-pathologist. The reported in Lancet 

1993,1998 Shivane et al., 2012 
Amoura et al., 2000 

Between 1993 and 1999 more than 50 cases of MMF have 
been described in France 

1999 Amoura et al., 2000 

MMF patient presents central nervous system disease 2001  Authier 2001 
Long term persistence of vaccine driven alum in muscle  2001 Gherardi et al., 2011 
MMF present local and systemic forms 2003 Papo 2003 
Electron microscopic study of MMF lesion description  2003-2005 Shmgdi et al., 2005 
Reporting MMF unrelated to vaccination 2005 Park et al., 2005 
Experimental induction of MMF in rats.TH1 bias response, 
TH1/TH2 balance unchanged in norma lesion size 

2006 Authier et al., 2006 

MMF being prove of vaccine autoimmune related disease 2011 Israeli et al., 2011 
Macrophage take up alum in tendon through fluerescent alum 
translocate to drainage lymph node then to blood, spleen and 
brain  

2012 Gherardi & Authier 
2012 

MMF several reports in UK 2012 Shivahe et al., 2012 
A report of an atypical presentation of MMF 2020 Dias et al., 2020 
Al (OH)3 vaccine associated with MMF pseudo-lymph node 
and causing hypersensitivity 

2020 Kim et al., 2020 

 

4. IMMUNOBIOLOGY 
 
Relatively, immune cells both naïve and active 
forms could be involved in immunobiology of 
MMF. Though the main player cells is the naïve 
and active macrophage. Autoreactive B cells are 
evidently involved, Autoreactive T cells are of 
unclear role. Modified macrophages of DC 
surface markers, modified morphology and 
modified function but still of macrophage 
morphotype are noted .TH1/Th2 are note 
changed and TH1 biased responses. These are 
the main immune-biological features  of MMF as 
presented in the following paragraphs. 
 
Alum nano-molecules may reach distant organs 
of the body including brain through the migration 
of the an alum loaded macrophage or though out 
diffusion process across the semipermeable 
membranes. This accompanied by an active liver 
detoxification of this chemical insult. Clearance of 
alum from the body have been found a species 
dependent process (Gherardi et al., 2019). Alum 
adjuvant induces humoral immune Th2 
responses via primary and secondary response 
events in mice and mixed humoral and cellular 
responses in human being whereby vaccine 
adjuvant supports the activation of CD8 T cells 
but these cells does not differentiated to cytotoxic 

T cells (Hogen-Esch 2013). In an in-vitro culture 
system Al(OH)2 stimulate isolated macrophages 
that contains large and persistent intracellular 
crystalline inclusion, the “Alum Loaded 
Macrophage ”ALM.ALM exhibit phenotypical and 
functional modifications as they showed myeloid 
dendritic cell surface markers[HLADR 
high,/CD1a-/CD14-] and displayed potent ability 
to induce MHC restricted antigen specific 
memory response but kept macrophage 
morphology. This suggest a key role of ALM in 
relation to the alum-vaccine and important role in 
this memory response (Ann-Ceclle et al., 2004). 
The vaccine alum adjuvant formulation when 
applied into the muscle, months to years later, 
the alum persists hidden in the inoculation site. 
Then released frequently in a steady state 
manner leading to chronic induction of immune 
reaction in the application site Macrophages and 
to lesser extent lymphocytes accumulate in the 
injection site took up alum nano-molecules may 
be through pinocytosis. Local granulomatous 
response is initiated and developed. In 
continuum with this local reaction alum may 
combined with self cellular protein from 
metalloprotein. A modified self protein such as a 
metalloprotein of MMP initiated specific immune 
and autoimmune responses in presence of the 
pathogenic allele HLADR 1 01 and the activated 



 
 
 
 

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tissue microenvironment as a pathology system. 
The net result of such reactions is the production 
of myo-specific autoantibody and CD8+T cell 
predominantly existed along with modified 
macrophages in the lesions (Shnawa 2023). This 
alum loaded modified macrophages my migrate 
through out blood stream to lymph nodes, spleen 
and brain by this they may lead to skeletal 
muscle and cognitive disorders (Gherardi et al 
2021). 
 
MMF has been reported after contact with metals 
and /or vaccines.it is typically occurs in 
individuals with genetic predisposition like 
HLADRB1 andPTPN22.Such contact may initiate 
over-immune reaction of the immune system that 
propriates to production of autoantibodies and 
fully cause autoimmune disorder. MMF is a sub-
entity of ASIA syndrome results from interaction 
between genetic and environmental factors with 
adjuvant through modulation receptors such as 
TLR, NLR and CLR triggering aberrant immune 
response prompting development of an 
autoimmune disorder (Caldarelli et al., 2024). 
Aluminum adjuvant is well known enhancer of 
TH2 responses. However, it has been suggested 
that Aluminum induces TH1 response in 
presence of other TH1 inducing compounds such 
as LPS or Rec. Influenza antigen, a bystander 
effect through which alum adjuvant trigger 
autoimmunity via activation of dormant 
autoreactive T lymphocyte in some individuals 
(Fan et al., 2022). 
 

5. MMF AUTOIMMUNE MECHANISMS 
 
In general autoimmune mechanisms are of 
classical and recent mosaic nature (Shnawa 
2023). MMF autoimmune mechanisms 
composed of a paradigm of three heritability 
features and four govering etiology roles (Li et 
al., 2015). As mentioned in the following 
paragraphs; 
 
Three main molecular mechanisms valid for 
explaining autoimmunity as; Tolerance, molecular 
mimicry and epitope spreading. Tolerance can be 
established through clonal deletion, anergy, 
clonal ignorance and regulatory T cell function 
(Perricon et al., 2019). The heritability of MMF 
has been well documented, quantified and 
exhibit three important features; I – all genetic 
diseases have strong genetic components, ii- 
relatively large numbers of risk alleles are shared 
between multiple autoimmune diseases and iii- 
the product of most of the autoimmune 
associated genes are parts of immunological 

pathways in particular T cell signaling, TNF 
signaling and innate immunity (Zherankova et al., 
2009). The reaction of the immune system to an 
environmental stimuli, produce autoimmune 
disease should pass four governing roles in a 
stepwise manner and start with; i-foundation of 
predisposing genetic architecture representing 
autoimmunity, ii- chronic repeated skewed and 
biased responses over years yield pathological 
system, iii- the pathological system induces loss 
of immune tolerance and iv- adopting nocuous 
potentials (Li et al., 2015, Zherankova et al., 
2009, Shnawa 2023). Hence, the proposed 
autoimmune mechanisms of the MMF are as 
follows; 
 

The genome of MMF patients has strong genetic 
component which is the autoimmune associated 
genes that contains large numbers of risk alleles. 
The gene expression products of these risk 
alleles are parts of the immunological pathway. 
Alum Chronic repetitive induction over years face 
the genome of the patient leading to a 
pathological system. Such pathological system 
induces loss of tolerance. Then affected immune 
system adopt nocuous potentials [molecular 
mimicry, antigen bystander and/or epitope 
spreading] the autoimmune condition. 
 

6. MMF IMMUNE FEATURES (Li et al., 
2015, Zherankova et al., 2009, Shnawa 
2023) 

 

The major immune features of MMF can be 
pointed out in the followings; 
 

i -Rare immune mediated disease 
 

ii – It is of an Inducive and constitutive nature. 
 

iii – Adjuvant-Alum driven. 
 

iv-Alum form metalloprotein a modified self 
protein. 
 

v-MMF macrophage appeared to useLC3 
associated phagocytosis to alum vaccine, and 
secret pain inducing molecules (Masson et al., 
2024). 
 

vi- Modified self protein, antigen bystander 
and/or molecular mimicry in presence of      
HLADR 1a 01 haplotype induce autoimmune 
response. 
 

vii-The nature of the autoimmune response in 
mice is humoral while in man is mixed humoral 
and cellular. 



 
 
 
 

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viii-Alum modified macrophage adopt new 
surface marker DC cells but they still of 
macrophage morphology. Such macrophage is 
believed to have a role in memory response. 
 
ix-TH1/TH2 balance found stable, but with bias 
TH1 response. 
 
x-Local muscle lesion nature is granulomatous. 
 
xi-The immune whole mark of ongoing reactions 
leads to functional problems in skeletal muscles 
and in cognition. 
 

7. DISEASE ENTITY 
 
The MMF is a rare macrophage driven myopathy. 
It stands as a molecular immunogenetic 
condition with an autoimmune presentation 
linked to HLADR 1a 01 susceptibility haplotype. 
MMF is grouped within the Shoenfeld’s 
Syndrome (Shoenfeld et al., 2011). 
 

8. LABORATORY IMMUNOLOGY 
 
Patient’s blood samples collect for the systemic 
humoral and cellular investigation. The humoral 
for check of myo-specific autoantibodies and for 
macrophage and T cell subsets. Biopsy sample 
for detection of the local cellularity nature of the 
granulomatous tissue reactions. Electron 
microscopic preparation from the lesion to 
elucidate the alum crystallization in cells. 
Immune laboratory animal model can be 
prepared to recheck the founding in man. 
 

9. LABORATORY ANIMAL IMMUNE 
MODELS 

 
Several number of laboratory animal models 
have been tempted by specialist workers in this 
field (Ruiz et al., 2017, Colafrancesco et al., 
2013). MMF lesions have been reproduced in; 
mice, rat, rabbit, monkeys and sheep by IV and 
IM routes. IV associated with rapid elimination. 
While, rabbit IM injection elimination lasts four 
weeks post injection (Gherardi et al., 2019). In an 
experimental animal setting, fluorescent nano-
tagged alum within the phagocyte have             
shown translocation of alum from the site of 
injection through blood circulation to the            
regional lymph nodes, spleen then to brain 
(Gherardi & Authier 2012). Spurg-Dully and 
Lewis rat injected with 10ul of AI(OH)3 adjuvant 
vaccine and watched over one year for the 
appearance of the lesions and the possible 
reduction of their sizes per time elapse. 

Shrinkage of the lesion size happened over time. 
Humoral Th2 and B cell immune responses 
mounted.TH1/Th2 balance. The function of 
cytotoxic T cell interferes with alum clearance 
process (Authier et al., 2006). 
 

10. ANIMAL IMMUNE MODEL 
SUGGESTION 

 
A group of 18 Spurg-Dully rats will be elected 
and grouped into three groups each of six. One 
sham saline control, one for alum solution a lone 
and one with vaccine -alum adjuvant. Rats of the 
three groups IM injected, and will follow up to 
score the lesions and possible reduction over 
time elapse. The formed lesions will be subjected 
to histopathological evaluations in month wise 
manner for six months. 
 

11. FACT SHEET (PARK ET AL., 2019, 
ISRAELI ET AL., 2011, CRUZ-TAPIAS 
ET AL 2013) 

 
Terminology: Macrophagic Myofasciitis. 
 
Disease Nature: Rare immune mediated liked to 
HALADR1*01 susceptibility haplotype. 
 

Onset Duration:3 months to eight years. 
 

Inducer: Vaccine-Alum formulation, or unknown 
 
Tissue Lesion Nature: Local sterio-typed 
immunologically active lesion. 
 

Histology: Tissue sections from biopsy made, 
stained with PAS searching for cellularity. 
 

Immunology: Determination of myo-specific 
autoantibodies in patients sera. 
 

Lesion Description: Infiltration of epimysium, 
perimysium, and perivascular endomysium with 
alum loaded PAS positive macrophage 
accumulation at the site of injection. Muscle 
necrosis is typically absent, spars CD8 T cells 
and minimal myofiber damage the lesion is of 
granulomatous nature (Gherhardi, Authier 2003). 
 

Chemical Analysis: Chemical microanalysis 
and atomic laser spectrophotometery reveals 
alum crystals within the macrophage. 
 

Systemic Reactions: Skeletal muscle and 
cognitive disorders (Israeli et al., 2011, Park et 
al., 2019). 
 
Age Prevalence: All ages. 



 
 
 
 

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102 

 

12. CONCLUSION 
 
MMF is an alum loaded macrophage driven 
autoimmune myopathy a syndrome sub-entity. It 
is linked with specific HLA haplotype 
susceptibility and grouped within Shoenfeld 
syndrome. MMF Immunobiology and 
autoimmune mechanisms, immune features and 
factsheet were issued. 
 

CONSENT 
 
It is not applicable. 
 

ETHICAL APPROVAL 
 

It is not applicable. 
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 
 

Author(s) hereby declare that NO generative AI 
technologies such as Large Language Models 
(ChatGPT, COPILOT, etc) and text-to-image 
generators have been used during writing or 
editing of this manuscript.  
 

COMPETING INTERESTS 
 

Author has declared that no competing interests 
exist. 
 

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