Tab Application Banner
  • Users Online: 577
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
EDITORIAL
Ahead of print publication  

Autoinflammation and autoimmunity: More to what meets the eye


1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Maulana Azad Medical College, Delhi, India
4 Department of Clinical Immunology and Rheumatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
5 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences; Department of Rheumatology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton; City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham; Division of Musculoskeletal and Dermatological Sciences, Centre for Musculoskeletal Research, School of Biological Sciences, The University of Manchester, Manchester, UK

Date of Submission10-Apr-2022
Date of Acceptance31-May-2022
Date of Web Publication07-Oct-2022

Correspondence Address:
Latika Gupta,
Department of Rheumatology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton WV10 0QP
UK
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_76_22



How to cite this URL:
Balakrishnan A, Mehta P, Sen P, Gupta V, Gupta L. Autoinflammation and autoimmunity: More to what meets the eye. Indian J Rheumatol [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=358026




  Introduction Top


Autoimmune and autoinflammatory disorders are both characterized by excessive undue activation of the immune system with autoimmune disorders primarily involving the adaptive immune arm of the immune system, whereas a dysregulated innate immune response is predominantly observed in autoinflammatory diseases.[1]

Autoimmunity involves loss of immune tolerance against specific self-antigens with reactive T- and B-lymphocytes and production of autoantibodies; the prototype autoimmune diseases being rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Conversely, autoinflammatory diseases are dominated by inflammation triggered by various environmental factors such as infections, temperature changes, and even mechanical stimuli on a fertile background of genetic predisposition. The classic autoinflammatory syndrome, familial Mediterranean fever (FMF), was first described in 1945 by Siega as a periodic fever with “benign paroxysmal peritonitis.”[2] The MEFV gene mutation was identified in 1997, paving the way for active research in the field of autoinflammatory syndromes and innate immunity.[3] With further research, the classification of autoinflammatory diseases has evolved, based on the operative dominant inflammatory pathways.[4]

However, attributing autoinflammation only to dysregulated innate immunity, and similarly asserting that adaptive immune involvement is the sole determinant of autoimmunity, is an oversimplification of the underlying pathophysiology. The innate and adaptive immune responses do not exist in isolation and mutual exclusion but instead act in conjunction. The innate immune system forms the first line of defense against danger signals and further activates the adaptive immune system. Similarly, autoinflammation and autoimmunity cannot be divided into absolute black and white, and an understanding of the various shades of gray is increasingly emerging.

It is now being recognized that apart from exclusive autoinflammatory disorders like periodic fever, the inflammasome-mediated mechanisms also play a role in diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), gout, diabetes mellitus, and atherosclerosis as well as in autoimmune diseases such as RA and SLE.[5],[6] Diseases such as spondyloarthritis (SpA) and inflammatory bowel disease (IBD) share features of both autoinflammatory and autoimmune disorders, and thus, the broad classification of autoinflammatory and autoimmune diseases often overlooks the mechanistic overlap between the two. Thus, the concept of “immunological disease continuum” was conceived.


  Classification continuum Top


The categorization of immunological diseases as a continuum was proposed by McDermott and McGonagle in 2006 on the principle that the disease phenotype depends on disturbances in the immune cells at the target site of inflammation rather than the immune system per se.[7] This continuum consists of monogenic autoinflammatory diseases at one end typified by dysfunction of the innate immune system (neutrophils and monocytes), monogenic autoimmune diseases at the other end characterized by dysfunction of the adaptive immune system (T- and B-cells), and a mixed pattern of diseases in the center [Figure 1].[1]
Figure 1: Autoimmunity and autoinflammation – the continuum

Click here to view


Autoinflammatory diseases at the far-left end of the spectrum are genetically determined and characterized by the rarity of occurrence and the absence of gender predilection. Whereas autoimmune disorders are characterized by polygenic etiology, female predominance and a progressive course with a rare occurrence of single gene defects. However, some diseases do not strictly follow these principles and lie at the center of this spectrum forming the classification continuum. There are polygenic autoinflammatory syndromes such as gout and adult-onset Still's disease which are characterized by episodic course, fever, arthritis, and a good response to interleukin (IL)-1 inhibition. At the extreme right, there are a group of monogenic autoimmune disorders such as immune dysregulation, polyendocrinopathy, and X-linked (IPEX) and autoimmune polyendocrinopathy, chronic candidiasis, and ectodermal dysplasia which have genetic defects in immune tolerance. At the center are diseases which show features of both autoinflammation and autoimmunity and are called mixed pattern diseases or “MHC-1-opathies.”


  Mixed pattern diseases or “MHC-1-opathies” Top


Mixed pattern diseases or MHC-1-opathies is an umbrella term that includes psoriasis, Behcet's disease (BD), and SpA spectrum of disorders [Figure 2]. This concept is unified by an association with class I MHC molecules, early age of onset with equal sex predilection, and a waxing and waning course. Most of these diseases occur as a result of mucosal barrier dysfunction and failure of immune stress surveillance.[8] SpA and BD are included in this group. Although Takayasu arteritis is also being suggested in this group, the exact pathophysiology is still unknown [Table 1].[9]
Figure 2: (a) MHC-1-opathies, (b) The model of danger theory, (c) Progression of systemic-onset juvenile idiopathic arthritis. PRR: Pattern recognition receptor, DAMPs: Damage-associated molecular patterns, APC: Antigen-presenting cell, ILC: Innate lymphoid cell, MAS: Macrophage activation syndrome, IL: Interleukin, TGF: Transforming growth factor

Click here to view
Table 1: Mixed pattern diseases

Click here to view


The immunology behind MHC-1-opathies is supported in wake of the danger model, which suggests that cellular injury and stress are more important determinants of immune system activation than the foreignness of the antigen [Figure 2]. Therefore, an immune response can be elicited by injured tissues by the release of certain “danger signals” even in the absence of an infectious agent.[10] Each of the concerned MHC1 has a predilection to affect certain tissues and hence confers risk for certain specific manifestations. For instance, HLA-B27 confers a risk for spondylitis, enthesitis, arthritis, aortitis, and eye involvement.[11] HLA-C06 is associated with skin involvement and HLA-B51 with eye, vessel, and skin involvement. The biomechanical stress, physical trauma as well as microorganisms can act as a trigger for the disease in these areas.

One of the pathogenetic mechanisms of HLA-B27 in ankylosing spondylitis is the formation of homodimers on cell surfaces owing to the unstable nature of HLA-B27. These homodimers then engage killer immunoglobulin-like receptors and leukocyte immunoglobulin-like receptors on natural killer cells and Th17 cells triggering activation of the innate and adaptive immune systems. Furthermore, the role of biomechanical stress has been exemplified by lower-limb predominant arthritis and enthesitis in humans, and this has been proven in animal studies.[12] Multiple reports have recently shown elevated B-cells in the peripheral blood, peripheral joints as well as the presence of antibodies such as anti-CD74, anti-14-3-3 eta, and anti-citrullinated vimentin paving the way for greater exploration of the autoimmune basis of the disease. These are attributed to primary genetic defects in the B-cell-associated genes or as a result of chronic inflammation-induced break in peripheral tolerance.[13]

Similarly, BD has a clinical profile similar to the SpA spectrum in the form of arthritis, skin involvement, oral ulcers, uveitis, and gastrointestinal involvement, which are indistinguishable from Crohn's disease.[14] In a subset of patients with BD who had acne and arthritis, ultrasonography showed increased enthesopathy scores, suggesting that BD may be closely related to SpA.[15] Genetic studies have suggested the role of both autoimmune and autoinflammatory pathways in the pathogenesis of BD.[16],[17] In a study from Turkey, the authors demonstrated an increased occurrence of SpA and BD in patients with FMF and their first-degree relatives.[18] In another study from Israel, the authors assessed the presence of FMF mutations in MHC-1-opathies and other autoimmune conditions and found that FMF mutations were seen in 1.2% of patients with psoriasis and Crohn's disease.[19]

Although MHC-1-opathies lack the classical features of autoimmunity, immunosuppressants, and anticytokine therapies form the cornerstone of therapy for these mixed pattern disorders. Colchicine has been effective for mucocutaneous BD, but more severe forms require immunosuppression. Thus, they classically fit into mixed pattern diseases with clinical features more akin to autoinflammatory diseases but pathology and treatment options such as autoimmune diseases.


  A few more gray areas Top


Despite a majority of diseases being successfully placed along the continuum, many diseases have not yet found a place due to their indeterminate fluidic nature, as well as significant lacunae in the understanding of the disease pathophysiology that exist in the current scenario. At times, certain inflammatory disorders may exhibit a biphenotypic pattern, wherein the inciting inflammatory event is autoinflammatory, but a gradual breach of tolerance and epitope spreading (potentially) leads to a shift toward an autoimmune spectrum later in the disease course. sJIA and AOSD begin as autoinflammatory diseases typified by fever and other systemic features, with IL-1 blocking therapies being very effective in the acute phase with an innate immunity-driven pathogenesis.[20] However, Th17-mediated responses take over in the later phase of the disease when systemic manifestations decline and erosive arthritis predominates.[21] The chronic phase of the systemic JIA can be concluded as an evolution of the disease from an autoinflammatory to an autoimmune phenotype according to this study [Figure 2].[22]

Similarly, palindromic rheumatism has been recognized as a relapsing–remitting variant of RA. It occurs as episodic and self-limiting arthritis involving one or more joints. Ultrasound studies have shown that palindromic rheumatism has a presence of periarthritis instead of active synovitis seen in RA.[23] One Spanish study showed the presence of MEFV mutations in 12.3% of patients with palindromic rheumatism.[24] These findings along with some success with colchicine favor it to be an autoinflammatory disorder. Similar involvement is also reported in intermittent hydrarthrosis, although the exact pathophysiology is largely understudied and poorly understood.[25],[26] Notably, the presence of autoantibodies and progression to RA in more than half of the patients with palindromic rheumatism makes it seem plausible that a subset was autoimmune to start with, Notably, a subset may have autoimmune origins as substantiated by the presence of autoantibodies and progression to RA in more than half of the patients. Further studies await a deeper understanding of the exact pathophysiologic origins in these cases at the crossroads of autoimmunity.[27]

The COVID-19 pandemic has brought us to the crossroads of autoimmunity and autoinflammation. The spectrum of COVID-19 (other than direct infection) is broad. It ranges from autoinflammatory syndromes in the acute phase like COVID cytokine storm and macrophage activation syndrome and the subacute phase like multisystem inflammatory syndrome to the emergence of autoimmunity in the form of laboratory evidence of autoantibodies such as ANA and antiphospholipid antibodies, as well as clinical syndromes in predisposed individuals. These syndromes may be systemic or organ-specific, and both short- and long-lasting autoimmunities have been observed. This itself forms an autoinflammation–autoimmunity continuum.

Among autoinflammatory diseases, the most intriguing of all is the multisystem inflammatory syndrome – children/adults. Although it shares some clinical features with Kawasaki disease, it has more gastrointestinal and systemic features. Mechanistically, it is driven by IL-10 and tumor necrosis factor-alpha with a possible role of multiple autoantibodies again making it difficult to classify.[28],[29],[30] The pathogenetic mechanisms of these are unclear. They are determined by factors such as age (with MIS-C being more common in children) and gender (myositis, arthritis, GBS, myelitis, and glomerulonephritis are reported mainly in men, whereas thyroiditis and pancreatitis occur more frequently in women). The most plausible mechanisms for induced autoimmunity and autoinflammation due to COVID-19 are a direct result of the viral trigger-molecular mimicry and bystander activation on the background of a genetic predisposition.[31] Certain HLA-B and HLA-C alleles and a cluster on chromosome 3p21 are risk factors for severe COVID-19.[32],[33] There is a striking similarity between COVID-19 hyperinflammation and anti-MDA5 dermatomyositis (melanoma differentiation antigen) in terms of rapidly progressive respiratory disease with hyperferritinemia and rashes throwing light on a plausible commune pathogenetic pathway. MDA-5 is part of the viral sensing machinery of the cell triggering a type I interferon response which can be triggered by both viral infections and antibodies.[34],[35],[36],[37],[38]


  Adding a third dimension? Top


Many autoinflammatory syndromes such as deficiency of adenosine deaminase 2, LUBAC deficiency, and APLAID as well as autoimmune diseases such as CTLA4 haploinsufficiency, CVID, and RAG1/2 deficiency are associated with concurrent immune deficiency. The updated classification of inborn errors of immunity has defined a separate subgroup for those with inherent susceptibility to autoimmunity as well as autoinflammation. These include autoimmune lymphoproliferative syndrome that presents with autoimmune cytopenias, autoimmune polyendocrine syndrome with antibodies to IL-17 resulting in immune deficiency, syndromes causing very early-onset IBD (IPEX), IL-10 deficiency, IL-10 R deficiency, etc., and those with general autoimmunity (CTLA4 and LRBA defects). Further, there is a higher prevalence of immunodeficiencies involving complement components and B-cells in adult-onset autoimmune diseases like SLE in certain ethnicities like Persians due to the high rate of consanguineous marriages. This aspect holds translational value with regard to therapeutics and may need replacement of complement components using fresh frozen plasma, IVIG, or avoidance of B-cell depleting therapy for B-cell immunodeficiency. Low copy numbers of C4A in SLE a study from Mexico have also been linked to a greater risk of infections. Some inborn errors immunity form an important third dimension in addition to autoimmunity and autoinflammation that helps us define the positions of various diseases better along the continuum.[39],[40],[41],[42]

Thus, in diseases other than monogenic diseases, innate and adaptive immune responses act in conjunction along a continuum, and not in mutual exclusion. This can be compared to the gene–environment continuum of characteristics of the human body, wherein some aspects like blood group are determined by a single set of genes, whereas skin complexion and eye color display a polygenic inheritance with environmental influence. [43, 44] A classification continuum based on these principles, representative of the underlying disease pathophysiology, would help classify many diseases in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med 2006;3:e297.  Back to cited text no. 1
    
2.
Adwan MH. A brief history of familial Mediterranean fever. Saudi Med J 2015;36:1126-7.  Back to cited text no. 2
    
3.
Pathak S, McDermott MF, Savic S. Autoinflammatory diseases: Update on classification diagnosis and management. J Clin Pathol 2017;70:1-8.  Back to cited text no. 3
    
4.
Barsotti S, Dastmalchi M, Notarnicola A, Leclaire V, Dani L, Gheorghe K, et al. Performance of the new EULAR/ACR classification criteria for idiopathic inflammatory myopathies (IIM) in a large monocentric IIM cohort. Semin Arthritis Rheum 2020;50:492-7.  Back to cited text no. 4
    
5.
Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med 2011;17:57-64.  Back to cited text no. 5
    
6.
Masters SL. Specific inflammasomes in complex diseases. Clin Immunol 2013;147:223-8.  Back to cited text no. 6
    
7.
McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res 2009;65:38R-45R.  Back to cited text no. 7
    
8.
Dalessandri T, Strid J. Beneficial autoimmunity at body surfaces – Immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer. Front Immunol 2014;5:347.  Back to cited text no. 8
    
9.
McGonagle D, Aydin SZ, Gül A, Mahr A, Direskeneli H. 'MHC-I-opathy'-unified concept for spondyloarthritis and Behçet disease. Nat Rev Rheumatol 2015;11:731-40.  Back to cited text no. 9
    
10.
Pradeu T, Cooper EL. The danger theory: 20 years later. Front Immunol 2012;3:287.  Back to cited text no. 10
    
11.
Ambarus C, Yeremenko N, Tak PP, Baeten D. Pathogenesis of spondyloarthritis: Autoimmune or autoinflammatory? Curr Opin Rheumatol 2012;24:351-8.  Back to cited text no. 11
    
12.
Masi AT. Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis? Arthritis Res Ther 2014;16:107.  Back to cited text no. 12
    
13.
Kollnberger S, Bird LA, Roddis M, Hacquard-Bouder C, Kubagawa H, Bodmer HC, et al. HLA-B27 heavy chain homodimers are expressed in HLA-B27 transgenic rodent models of spondyloarthritis and are ligands for paired Ig-like receptors. J Immunol 2004;173:1699-710.  Back to cited text no. 13
    
14.
Direskeneli H. Autoimmunity vs. autoinflammation in Behcet's disease: Do we oversimplify a complex disorder? Rheumatology (Oxford) 2006;45:1461-5.  Back to cited text no. 14
    
15.
Hatemi G, Fresko I, Tascilar K, Yazici H. Increased enthesopathy among Behçet's syndrome patients with acne and arthritis: An ultrasonography study. Arthritis Rheum 2008;58:1539-45.  Back to cited text no. 15
    
16.
Puccetti A, Fiore PF, Pelosi A, Tinazzi E, Patuzzo G, Argentino G, et al. Gene expression profiling in Behcet's disease indicates an autoimmune component in the pathogenesis of the disease and opens new avenues for targeted therapy. J Immunol Res 2018;2018:4246965.  Back to cited text no. 16
    
17.
Wu Z, Zhang S, Li J, Chen S, Li P, Sun F, et al. Association between MEFV mutations M694V and M680I and Behçet's disease: A meta-analysis. PLoS One 2015;10:e0132704.  Back to cited text no. 17
    
18.
Akar S, Soysal O, Balci A, Solmaz D, Gerdan V, Onen F, et al. High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: Further evidence for the connection. Arthritis Res Ther 2013;15:R21.  Back to cited text no. 18
    
19.
Watad A, Bragazzi NL, Adawi M, Shoenfeld Y, Comaneshter D, Cohen AD, et al. FMF is associated with a wide spectrum of MHC class I- and allied SpA disorders but not with classical MHC class II-associated autoimmune disease: Insights from a large cohort study. Front Immunol 2019;10:2733.  Back to cited text no. 19
    
20.
Nigrovic PA. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 2015;112:15785-6.  Back to cited text no. 20
    
21.
Nigrovic PA. Review: Is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol 2014;66:1405-13.  Back to cited text no. 21
    
22.
Hügle B, Hinze C, Lainka E, Fischer N, Haas JP. Development of positive antinuclear antibodies and rheumatoid factor in systemic juvenile idiopathic arthritis points toward an autoimmune phenotype later in the disease course. Pediatr Rheumatol Online J 2014;12:28.  Back to cited text no. 22
    
23.
Cabrera-Villaba S, Garcia JR, Salvador G, Ruiz-Esquide V, Hernández MV, Saura C, et al. SAT0015 searching for subclinical synovitis in palindromic rheumatism: An ultrasound study in 40 patients. Ann Rheum Dis 2013;72 Suppl 3:A584.  Back to cited text no. 23
    
24.
Cañete JD, Arostegui JI, Queiró R, Gratacós J, Hernández MV, Larrosa M, et al. An unexpectedly high frequency of MEFV mutations in patients with anti-citrullinated protein antibody-negative palindromic rheumatism. Arthritis Rheum 2007;56:2784-8.  Back to cited text no. 24
    
25.
Klippel JH, Stone MJ, Crofford ML, White MP. Primer on Rheumatic Disease. 13th ed. Springer, New York. 2008.  Back to cited text no. 25
    
26.
Queiro-Silva R, Tinturé-Eguren T, López-Lagunas I. Successful therapy with low-dose colchicine in intermittent hydrarthrosis. Rheumatology (Oxford) 2003;42:391-2.  Back to cited text no. 26
    
27.
Schwartzberg M. Prophylactic colchicine therapy in palindromic rheumatism. J Rheumatol 1982;9:341-3.  Back to cited text no. 27
    
28.
Galeotti C, Bayry J. Autoimmune and inflammatory diseases following COVID-19. Nat Rev Rheumatol 2020;16:413-4.  Back to cited text no. 28
    
29.
Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with covid-19. N Engl J Med 2020;382:e38.  Back to cited text no. 29
    
30.
Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 2020;183:968-81.e7.  Back to cited text no. 30
    
31.
Rodríguez Y, Novelli L, Rojas M, De Santis M, Acosta-Ampudia Y, Monsalve DM, et al. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. J Autoimmun 2020;114:102506.  Back to cited text no. 31
    
32.
Wang W, Zhang W, Zhang J, He J, Zhu F. Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19). HLA 2020;96:194-6.  Back to cited text no. 32
    
33.
Severe Covid-19 GWAS Group, Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med 2020;383:1522-34.  Back to cited text no. 33
    
34.
Gupta R, Kumar S, Gow P, Hsien-Cheng Chang L, Yen L. Anti-MDA5-associated dermatomyositis. Intern Med J 2020;50:484-7.  Back to cited text no. 34
    
35.
Dunga SK, Kavadichanda C, Gupta L, Naveen R, Agarwal V, Negi VS. Disease characteristics and clinical outcomes of adults and children with anti-MDA-5 antibody-associated myositis: A prospective observational bicentric study. Rheumatol Int 2022;42:1155-65.  Back to cited text no. 35
    
36.
Mehta P, Machado PM, Gupta L. Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry. Rheumatol Int 2021;41:1021-36.  Back to cited text no. 36
    
37.
Smatti MK, Cyprian FS, Nasrallah GK, Al Thani AA, Almishal RO, Yassine HM. Viruses and autoimmunity: A review on the potential interaction and molecular mechanisms. Viruses 2019;11:762.  Back to cited text no. 37
    
38.
Gupta P, Kharbanda R, Lawrence A, Gupta L. Systemic flare and cutaneous ulceration following cytomegalovirus infection in a patient with anti-melanoma differentiation-associated protein 5 (MDA5) associated myositis: Diagnostic challenge during the time of coronavirus disease (COVID-19) pandemic. Egypt Rheumatol 2021;43:271-4.  Back to cited text no. 38
    
39.
Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 Update of the IUIS phenotypical classification. J Clin Immunol 2020;40:66-81.  Back to cited text no. 39
    
40.
Savic S, Caseley EA, McDermott MF. Moving towards a systems-based classification of innate immune-mediated diseases. Nat Rev Rheumatol 2020;16:222-37.  Back to cited text no. 40
    
41.
Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: The molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol 2009;27:621-68.  Back to cited text no. 41
    
42.
Rezaei N, Mohammadinejad P, Aghamohammadi A. The demographics of primary immunodeficiency diseases across the unique ethnic groups in Iran, and approaches to diagnosis and treatment. Ann N Y Acad Sci 2011;1238:24-32.  Back to cited text no. 42
    
43.
Jüptner M, Flachsbart F, Caliebe A, Lieb W, Schreiber S, Zeuner R, et al. Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus. Lupus 2018;27:600-9.  Back to cited text no. 43
    
44.
Adhikari K, Mendoza-Revilla J, Sohail A, Fuentes-Guajardo M, Lampert J, Chacón-Duque JC, et al. A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia. Nat Commun 2019;10:358.  Back to cited text no. 44
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Balakrishnan A
    -  Mehta P
    -  Sen P
    -  Gupta V
    -  Gupta L
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Introduction
Classification c...
Mixed pattern di...
A few more gray ...
Adding a third d...
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed823    
    PDF Downloaded10    

Recommend this journal