Immunodeficiency and Autoimmunity: Lessons from Systemic Lupus

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Review

Immunodeﬁciency and autoimmunity:

lessons from systemic lupus

erythematosus

Alexandros P. Grammatikos and George C. Tsokos

Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

Recent evidence suggests that systemic autoimmunity and a phenotype associated with infections by speciﬁc

and immunodeﬁciency are not separate entities, but microbial agents have recently been reported [6]. Examples

rather are interconnected processes. Immunodeﬁciency are patients with late complement component deﬁciencies

results from distinct defects of the immune response and who are particularly prone to infection with Neisseria

primarily presents as infections but also frequently with

autoimmune features. Systemic autoimmunity is the Glossary

combined effect of multiple genetic variations and

Adrenocortical failure: insufficiency of the cortical part of the adrenal gland,

infectious and immunoregulatory factors that result in which is responsible for the production of corticosteroids, aldosterone and

androgenic steroids. This can be caused by many factors, including infections,

dominant autoimmune manifestations, in addition to

emboli, and tumors.

frequent and opportunistic infections. The overlap in

Agammaglobulinemia (or hypogammaglobulinemia): absence, or very low

disease manifestations and symptoms suggests that levels, of immunoglobulins (antibodies), resulting in the development of

multiple infections.

immunodeﬁciency should be considered in the presence

Atopy: inherited predisposition that causes a tendency to suffer from one or

of autoimmunity, and vice versa. In this review, we

more allergic diseases, such as asthma, rhino-conjunctivitis and dermatitis.

present the shared or similar aspects of immunodeﬁ- Autoimmune thrombocytopenia: a disorder involving low blood platelet count

in which platelets are destroyed by antibodies produced by the immune system.

ciency and autoimmunity using systemic lupus erythe- +

CD4 T helper cells: are cells responsible for orchestrating the immune

matosus as a paradigm and discuss the implications for

response and providing signals for the activation of other immune cells, such

clinical care. as B and cytotoxic T lymphocytes.

Chronic mucocutaneous candidiasis: a group of disorders characterized by

recurrent or persistent infections of the skin, mucous membranes, and nails

The basis of systemic lupus erythematosus

with Candida organisms.

Systemic lupus erythematosus (SLE) is an immune complex Granuloma: a mass or nodule of inflamed tissue characterized histologically by

transformed macrophages (epithelioid cells) surrounded by lymphocytes.

disease that predominantly affects women of reproductive

Granulomatosis with polyangiitis (Wegener’s): a vasculitic disorder character-

age. Multiple autoantibodies are produced that bind diverse

ized by inflammation (vasculitis) of small and medium blood vessels and the

nuclear antigens, including double-stranded DNA, RNP presence of granulomas, mainly in sinuses, lungs, and kidneys.

Hemophagocytic lymphohistiocytosis (HLH): a syndrome characterized by

(ribonucleoproteins) and Sm (Smith). These autoantibodies

fever, hepatosplenomegaly, and lymphadenopathy due to uncontrolled cyto-

deposit on several organs, including kidneys, skin and

toxic T cell activation and tissue infiltration with histiocytes (macrophages).

joints, causing inﬂammation [1]. The etiology of SLE has Hepatosplenomegaly: simultaneous enlargement of both the liver and spleen.

Hypergammaglobulinemia: presence of elevated levels of immunoglobulins

still not been clearly elucidated, but a strong genetic contri-

(belonging to the gamma globulin fraction in serum electrophoresis) in blood

bution to disease development is postulated to exist. Gene serum. Can be polyclonal (multi-epitope-specific, as seen in chronic inflam-

polymorphisms, single nucleotide polymorphisms (SNPs), matory conditions) or monoclonal (specificity for a single epitope).

Hypoparathyroidism: a disease characterized by decreased function of the

gene deﬁciencies and duplications, and aberrant expression

parathyroid glands, responsible for the production of parathyroid hormone

of splice variants have all been identiﬁed as contributing to and body calcium homeostasis.

Lymphadenopathy: enlargement of lymph nodes.

the expression of SLE in certain individuals [2]. Genome-

Lymphoid interstitial pneumonia: a syndrome of fever, cough, and dyspnea

wide association studies (GWAS) performed in SLE patients

owing to dense accumulations of lymphocytes at the alveolar interstitium.

have identiﬁed intriguing links between genetic diversity in Midline granulomatous disease: a disease characterized by necrotizing

granulomas of the head and neck. It is most commonly caused by

major components of the immune system and susceptibility

granulomatosis with polyangiitis disease, natural killer or T cell lymphomas,

to SLE [3]. What is even more interesting is that genetic

cocaine abuse, or infections.

variations in genes previously associated with immunodeﬁ- Molecular mimicry: sequence similarities between foreign and self-peptides

that allow for the development of cross-reactive T or B cells and autoimmunity.

ciency are now also linked to SLE [4,5]. Complete under-

Pancytopenia: reduction in the number of all blood cell subpopulations (red

standing of gene involvement in the expression of the

blood cells, white blood cells and platelets).

disease may improve our understanding of the pathways Plasmacytoid dendritic cells: one of the two principal subsets of human

dendritic cells (DCs) with a plasma cell-like morphology.

used by pathogens and other environmental contributors to

Polyangiitis: inflammation involving multiple blood or lymph vessels.

disease pathology [6,7].

Ribosomopathies: collection of disorders in which genetic abnormalities cause

Several cases in which monogenic defects in genes encod- impaired ribosome biogenesis and function, such as Diamond–Blackfan

anemia, Shwachman–Diamond syndrome, X-linked dyskeratosis congenita,

ing immune system components lead to immunodeﬁciency

cartilage hair hypoplasia, and Treacher Collins syndrome.

Sarcoid-like granulomas: granulomas that do not display necrosis and are

surrounded by concentric scar tissue (fibrosis).

Corresponding author: Grammatikos, A.P. ([email protected]).

Review Trends in Molecular Medicine February 2012, Vol. 18, No. 2

Environmental factors

UV light, stress, chemicals/drugs, diet (iii ) Reactive immune (i) (ii) system expansion Subclinical infections Mild immune system defect

Genetic factors Autoimmunity Epigenetic contributions -other genetic defects

TRENDS in Molecular Medicine

Figure 1. Immune system defects and autoimmunity. The development of multiple subclinical infections may represent the triggering event in autoimmune patients that

leads to uncontrolled immune system activation and chronic inflammation. A decline in immunity triggered by environmental factors (e.g. diet or psychological effectors) in

combination with the presence of mild immune system defects may allow these infections to develop.

meningitidis, the causative agent of meningitis [8], Toll-like

Box 1. Spread of inflammation and development of

receptor 3 (TLR3)-deﬁcient individuals, who are prone to

systemic autoimmunity

herpes simplex virus (HSV) encephalitis [9], and MyD88-

The higher number of infections that affect patients with SLE could

deﬁcient patients, who are prone to invasive pneumococcal

contribute to the development of systemic inflammation. Epitope

disease [10].

spreading, superantigen activation, and bystander activation are

some of the mechanisms through which the spread of the

Immune defects in SLE inflammatory response can occur.

Primary immunodeﬁciency syndromes (PIDs) result from 1. Epitope spreading Antigen-presenting cells (APCs) that recognize

a viral epitope internalize the whole protein and not just the

distinct defects of immune genes, whereas in SLE, besides

specific epitope, allowing them to present many different types of

rare cases such as C1q and C4 deﬁciencies, widespread

antigenic determinants to T cells [78]. In this way, multiple T-cell

SNPs and gene variants appear to contribute subtly to

specificities can be generated from a single epitope, allowing for

aberrant immune system function [11]. Thus, weakly con- the subsequent activation of multiple B cell clones [79]. Under

physiological conditions, epitope spreading is beneficial in that it

tributing genetic factors allow ample space for environ-

allows for the generation of a rapid and robust immune response

mental inﬂuences (e.g. infections, diet or psychology) [12]

from a single antigenic determinant. However, it can also

and other factors to contribute to the manifestation of

function in a harmful manner by leading to the generation of

autoimmunity and related pathology (Figure 1). autoreactive cells. The fact that multiple antibody specificities

SLE patients experience a high rate of infections, even accrue over time in SLE, so that the average number of

autoantigens recognized gradually increases, suggests that

from opportunistic pathogens normally observed in im-

epitope spreading might indeed occur early on in the course of

munocompromised individuals, such as Toxoplasma gon-

this disease [80].

dii, Pneumocystis carinii and Cryptococcus neoformans

2. Superantigen activation Several bacterial pathogens, such as

[13]. There is increasing evidence that these infections, Staphylococcus and Mycoplasma, exhibit superantigen proper-

at both a clinical and subclinical level, may represent the ties. Superantigens have the unique capacity to cross-link several

T cell receptors, and thus activate many different antigenic

primary trigger for constant immune system activation

specificities synchronously [81,82]. Again, not only are immune

and autoimmunity (Figure 1) [14,15]. Infection causes

responses against pathogens enhanced by this process, but self-

neutrophils to form web-like structures, the so-called

reactive clones can also be generated [83]. Evidence for the

neutrophil extracellular traps (NETs) [16]. Increased for- involvement of superantigens in the pathogenesis of two other

mation of NETs has been reported in SLE, although this autoimmune diseases, experimental autoimmune encephalo-

myelitis (EAE) and inflammatory bowel disease, has been

formation has not been linked to a speciﬁc infection

produced.

[17,18]. Several pathways have been described that allow

3. Bystander activation Apart from engulfing microbial particles,

an immune response against a particular microbial agent

APCs in the inflammatory microenvironment also take up

to develop into generalized immune system activation and apoptotic material from host cells that are present. Peptides

from this material can then be presented to T cells and, in the

autoimmunity (Box 1).

context of inflammation, autoreactive T cell clones can be

In a genetically predisposed individual, exposure to

generated [84,85].

environmental factors may be chronic and begin long

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before disease development, as can be concluded from reactive immune cell activation could underlie the high

reports that autoantibodies appear several years prior to IFN production. Indeed, high numbers of inﬁltrating plas-

disease diagnosis [19]. Increased susceptibility to infection macytoid dendritic cells (pDCs), one of the major producers

in patients with SLE [20] may very well exist before the of type I IFNs, are observed in skin and renal lesions from

development of clinical disease and during the long period SLE patients [23,24]. Furthermore, pathogen-associated

of preexisting autoimmunity. Exposure to infections and nucleic acids seem to be able to exacerbate SLE pathology

other environmental factors occurs in a discontinuous [21]. Cultured mesangial cells that are exposed to synthetic

fashion and may fuel the immune system, causing a dis- polyinosinic–cytidylic acid (pI:C) RNA in vitro produce

ease ﬂare [13,21]. CCL2 as well as IL6, and in vivo injection of pI:C RNA

increases serum IL-12p70, IL6, and IFN-a levels.

Infections implicated in the pathogenesis of SLE One candidate viral pathogen implicated in SLE immu-

One characteristic of SLE is the ‘interferon (IFN) signa- nopathogenesis is the Epstein–Barr virus (EBV). Infec-

ture’, a signiﬁcant upregulation of type I IFN-inducible tious mononucleosis caused by EBV exhibits similar

genes (IFN-a and IFN-b) in peripheral blood cells [22], epidemiologic characteristics as SLE, in that they both

which suggests the presence of high levels of IFN-a and afﬂict young adults, are less common in areas where

IFN-b cytokines (Box 2). The IFN signature seems to primary EBV infection is endemic, and follow the same

strongly support the idea that a chronic viral infection is geographic latitude gradient [25]. Once infected, SLE

involved in the pathogenesis of SLE. An immune system patients seroconvert to EBV faster than controls and the

defect that allows uncontrolled viral proliferation and EBV load is higher in SLE-affected individuals [26]. In a

Box 2. Type I interferon (IFN) production pathways

Plasmacytoid dendritic cells (pDCs) represent one of the major and TLR9 receptors, respectively [87]. CNARs, by contrast, are present

sources of IFN-a. These cells carry pattern-recognition receptors in all nucleated cells and allow recognition of viral particles directly at

(PRRs) that are able to recognize evolutionarily conserved structures their point of entry. Examples of such receptors include RIG-I (retinoic

on infectious microorganisms as ‘foreign’ and trigger an immune acid-inducible gene I), MDA5 (melanoma differentiation-associated

system reaction against them (Figure I). Two different types of PRRs gene) and DAI (DNA-dependent activator of IFN-regulatory factors)

are involved in this process, TLRs (Toll-like receptors) and CNARs [88]. When either of these two pathways is activated, the end result is

(cytosolic nucleic acid receptors). the production of type I IFNs. Binding of IFNs to their respective

Located in endosomal compartments, TLRs scan phagocytosed receptors on infected cells allows the latter to activate intracellular

material for the presence of viral particles [86,87]. Single-strand RNA pathways that limit pathogen replication and promote clearance.

and double-strand DNA from viral particles are recognized by TLR7 Viruses /bacteria

dsDNA TLR7

TLR9 ssRNA Antiviral Endosome IFNα / IFNβ responses

RIG-I MDA-5

DAI Infected cell

pDC

TRENDS in Molecular Medicine

Figure I. Type I interferon production. Toll-like receptors (TLRs) in endosomal compartments and cytosolic nucleic acid receptors (CNARs) scan phagocytosed material

for the presence of viral particles. Upon recognition of their respective ligands, type I interferons responsible for activating intracellular pathways that promote

pathogen clearance are produced (IFN-a and IFN-b).

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Table 1. Immunodeﬁciency and associated autoimmune diseases

Disease Defective molecule (involved in) Infectious manifestations Autoimmune or lymphoproliferative Refs

manifestations

FHL Perforin gene (T and NK cell cytotoxicity) Increased viral infections HLH (inﬂammation and tissue destruction) [34]

XLP SLAM-associated protein (SAP) (CD8 T Uncontrolled EBV infection HLH (inﬂammation and tissue [29,30]

and NK cell signaling pathways) destruction), lymphoma

WAS WAS protein (WASP) (actin cytoskeleton) Recurrent bacterial infections ITP, AHA, vasculitis, eczema, lymphoma [67]

CGD NADPH oxidase (neutrophil bactericidal Recurrent bacterial and/or Chronic gut and/or lung inﬂammation [64]

mechanisms) fungal infections

MGD RAG1, RAG2 (somatic rearrangement of Systemic viral infections Caseating granulomas of the nose, [65,66]

Ig and TCR genes) (CMV, EBV, VZV) sinuses, palate, and upper airways

APECED AIRE gene (deletion of autoreactive Candidiasis Organ-speciﬁc autoimmunity [69]

lymphocyte clones) (parathyroid, adrenals)

CVID TACI, ICOS, BAFFR, CD19, and MSH5 Recurrent sinopulmonary and IBD, ITP, AHA, LIP, lymphoma [72,73]

genes (antibody production) GIT infections

IgAD IgA antibody production Recurrent infections SLE, rheumatoid arthritis, ITP, [71,70]

allergy, asthma

XLA Btk (B cell development and signaling) Recurrent infections Arthritis, AHA, scleroderma, [74]

type 1 diabetes

Abbreviations: FHL, familial hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; XLP, X-linked lymphoproliferative syndrome; SLAM,

signaling lymphocyte-activation molecule; EBV, Epstein–Barr virus; WAS, Wiskott–Aldrich syndrome; ITP, immune thrombocytopenia; CGD, chronic granulomatous

disease; NADPH, nicotinamide adenine dinucleotide phosphate; MGD, midline granulomatous disease; RAG, recombination activating genes; Ig, immunoglobulin; TCR, T

cell receptor; CMV, cytomegalovirus; VZV, varicella-zoster virus; APECED, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; AIRE, autoimmune

regulator; CVID, common variable immunodeﬁciency; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor; ICOS, inducible T-cell

costimulator; BAFFR, B cell-activating factor receptor; MSH5, MutS protein homolog 5; GIT, gastrointestinal tract; IBD, inﬂammatory bowel disease; AHA, autoimmune

hemolytic anemia; LIP, lymphoid interstitial pneumonia; IgAD, IgA deﬁciency; XLA, X-linked agammaglobulinemia; Btk, Bruton’s tyrosine kinase.

study performed in young adult lupus patients, 99% of Defective immune response and pathogen clearance in

them had antibodies against EBV antigens in peripheral SLE

blood, compared with only 70% of their matched controls SLE patients exhibit several immune defects that involve

[27]. It appears that SLE CD8 T cells cannot effectively both the innate and adaptive immune pathways. In many

respond to EBV-infected B cells, as demonstrated by the cases, these affect proper pathogen recognition and/or

fact that very low proportions of EBV-speciﬁc CD8 T cells clearance.

are able to produce IFN-g in SLE patients in comparison

with controls [28]. T cells and NK cells

An association between EBV infection and autoimmu- CD8 T cells, one of the most important players in antiviral

nity has already been established for X-linked lympho- immune defense, exhibit defective cytolytic abilities in

proliferative syndrome (XLP). XLP, a disease due to patients with SLE, a defect that has not been found in

deﬁciency of the SLAM-associated protein (SAP), is char- any other autoimmune disease [32]. Lack of perforin leads

acterized by chronic inﬂammatory responses and a hemo- not only to defective pathogen clearance but also to accel-

phagocytic lymphohistiocytosis picture (Table 1) [29]. erated humoral autoimmunity and lupus-like disease in

SAP is known to be part of signaling pathways in T cells mice [33]. A similar situation has been reported in humans,

and natural killer (NK) cells, and its absence seems to where complete loss of perforin function presents as famil-

result in an inability to counteract acute EBV infection, ial hemophagocytic lymphohistiocytosis (FHL), a fatal au-

which leads to the chronic inﬂammation observed in these toimmune disorder of early childhood [34]. CD8 T cell

patients [30]. responses against EBV, one of the potential candidates for

An association between parvovirus B19 infection and SLE pathogenesis, are decreased in patients with SLE [35]

SLE has also been reported. Parvovirus B19 DNA and IgM and these patients have fewer IFN-g-producing cells

anti-B19 antibodies have been reported in a small groups against inﬂuenza virus A H1N1 strain compared with

of patients and it has been proposed that an undeﬁned control subjects [36].

molecular mimicry is the linking mechanism [31]. CD4 T helper cells also seem to be dysfunctional in SLE

Despite the presence of several lines of evidence sug- patients and exhibit an aberrant helper activity [37]. IL2

gesting the involvement of infectious agents in SLE immu- production from CD4 T helper cells, required for the

nopathogenesis, there are a number of reasons why differentiation and survival of antigen-speciﬁc CD8

distinct infectious agents causing SLE may never be found: T cells, is decreased in SLE patients [38]. Reduced CD4

(i) it is difﬁcult to track individuals who are predisposed to T cell responses against varicella zoster virus and a higher

develop SLE and observe the events they experience before incidence of herpes zoster infection are also observed [39].

becoming ill; (ii) the pathogenesis of SLE is probably the Furthermore, T helper cell responses against recall anti-

+ +

result of different factors acting together over time or gens are decreased in SLE patients. Both CD4 and CD8

simultaneously; (iii) more than one infectious agents T cells display increased rates of spontaneous apoptosis in

may be involved; and (iv) the pathogen responsible may SLE patients [40], leading to decreased cell numbers and a

be an as yet unidentiﬁed infectious agent. decreased immune defense repertoire.

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The decreased CD3z chain expression observed in SLE MHC-I deﬁciency (bare lymphocyte syndrome) sometimes

patients could explain some of the above ﬁndings [1,2]. The exhibit autoimmune phenomena reminiscent of granulo-

CD3z chain constitutes part of the T-cell receptor (TCR) matosis with polyangiitis [52]. Lupus-prone mice with b2

signaling machinery and is responsible for transmitting microglobulin deﬁciency (a component of MHC-I) exhibit

downstream signals upon antigen recognition. Lack of accelerated skin disease [53]. MHC-I is required for the

CD3z expression could contribute to the defective immune detection of intracellular pathogens by CD8 T cells, and

responses against infections observed in SLE. Consistent its absence seems to lead to a failure to defend against such

with this, defective TCR signaling has been shown to lead pathogens. A certain gene transcription signature in CD8

to the development of a lethal, multiorgan autoimmune T cells has been linked to SLE disease prognosis [54].

disease in mice [41]. Mutations in the gene encoding for Similarly, patients with ribosomopathies commonly

ZAP70, a downstream signaling target of the CD3z com- present features of immune deﬁciency [55]. Ribosomopa-

plex, also lead to the development of autoimmunity in mice thies are a diverse collection of genetic disorders leading to

[42]. Infectious agents seem to play an important role bone marrow failure, typical examples of which are Dia-

because mice bred in a microbial-free environment do mond–Blackfan anemia (DBA) and Shwachman–Diamond

not develop autoimmunity [43]. syndrome (SDS). Several immune defects have been de-

Finally, the number of NK cells, another key player in scribed in these patients, including low numbers and

the defense against viral infections, is also decreased in reduced function of both T cells and B cells. Low expression

SLE patients [44]. Overall, these defects suggest inade- levels of ribosome-related genes in SLE patients could have

quate antiviral immunity in SLE patients. This could be similar effects on the immune system, making the clear-

responsible for the spread of multiple viral infections, both ance of pathogens less effective.

at a clinical and a subclinical level.

B cells

Complement B cells from patients with SLE are characteristically poly-

Complement deﬁciencies, a distinct group of immunodeﬁ- clonally activated and produce autoantibodies against a

ciencies, provide a perfect background for the development large array of self-antigens [1]. Lower numbers of naı¨ve B

of both autoimmunity and infections. Early complement cells and higher numbers of antibody-producing plasma

component deﬁciency frequently leads to the development cells are routinely recorded [56].

of autoimmunity and autoimmune-like manifestations Certain autoantibodies have been linked to pathology,

(93% of individuals with C1q deﬁciency, 60–66% of indi- yet IgM autoantibodies may have a protective role [57].

viduals with C1 s or C1r deﬁciency, 90% of individuals with The fact that lupus-prone mice that lack soluble antibodies

C4 deﬁciency and 10% of individuals with C2 deﬁciency) still develop lupus-like disease supports the idea that SLE

[45]. Lack of C1 inhibitor, responsible for the development pathology may occur independently of soluble autoantibo-

of angioedema, has been linked in some cases to lupus dies [58]. Indeed, instead of hypergammaglobulinemia,

nephritis and other autoimmune manifestations [46]. Late decreased immunoglobulin levels or even typical combined

complement factor deﬁciencies, by contrast, are linked variable immunodeﬁciency (CVID) [59,60] is observed in

preferentially to infections and not to autoimmunity [47]. some SLE patients. As many as 6% of SLE patients display

Decreased expression of complement receptor 1 (CR1), concurrent IgA deﬁciency, and the same drugs that have

the complement receptor for C3B, on erythrocytes, poly- been associated with this have also been associated with

morphonuclear cells and B cells in SLE patients may the development of SLE (e.g. phenytoin, D-penicillamine

account for the defective phagocytic capacity toward infec- and sulfasalazine) [61].

tious microorganisms [48]. This is probably accentuated in

certain patients who carry the R77H allele of ITGAM Other cell types

(which encodes Mac-1, also known as CR3). One of the Both monocytes and macrophages from SLE patients ex-

Mac-1 ligands is C3bi, and therefore, complement-depen- hibit increased levels of apoptosis. Furthermore, mono-

dent opsonization and phagocytosis are compromised in cytes exhibit decreased levels of FcRII and FcRIII

these patients [49]. receptors on their surface membrane in SLE patients,

Decreased mannose-binding lectin (MBL) is the most and both are necessary for the phagocytosis of foreign

common immunodeﬁciency in humans, with 5% of the and apoptotic material [62]. Monocyte-derived DCs from

population affected. Although the phenotype of this deﬁ- patients with SLE also exhibit diminished phagocytic

ciency is usually mild, an increased prevalence of SLE has capacity associated with decreased expression of speciﬁc

been reported in these patients [50]. Similar to the case of C-type lectin receptors on their surface [63].

early complement components of the classical pathway,

both rheumatic manifestations and higher rates of infec- Autoimmune manifestations in immunodeﬁciency

tions are observed in patients suffering from MBL deﬁ- diseases

ciency. Clinical and laboratory ﬁndings consistent with autoim-

munity are common in immunodeﬁcient patients (Table 1).

MHC-I and ribosomal genes The decreased ability of the immune system to clear infec-

Microarray studies performed in SLE patients have tions in these patients can cause perpetual immune-sys-

revealed that major histocompatibility complex class I tem activation and autoimmunity.

(MHC-I) and ribosomal-related genes are underexpressed Familial hemophagocytic lymphohistiocytosis (FHL)

compared with controls [51]. Conversely, patients with is an autosomal recessive PID in which a defect in

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perforin excretion has been documented [34]. Lack of [72]. Autoimmune diseases such as inﬂammatory bowel

perforin deprives the immune system of one of its main disease (IBD), autoimmune thrombocytopenia and thyroid

effectors against viral infections. In response to multiple disease are frequently present [73], and lymphoprolifera-

uncleared viral infections, an overwhelming activation of tive diseases, including lymphoid interstitial pneumonia,

T lymphocytes and macrophages as well as persistent sarcoid-like granulomas and even lymphoma, are frequent-

inﬂammatory responses are seen in these patients. As a ly observed.

consequence, multiple autoimmune phenomena develop, In X-linked agammaglobulinemia (XLA) patients, iden-

including pancytopenia, rashes, lymphadenopathy and tiﬁed by low or absent B cells and low immunoglobulin

hepatosplenomegaly. levels, many autoimmune diseases are present, including

In chronic granulomatous disease, where there is de- arthritis, autoimmune hemolytic anemia, scleroderma and

creased production of NADPH oxidase by neutrophils, type 1 diabetes mellitus (T1DM), in addition to chronic

recurrent bacterial and fungal infections develop, fol- and/or recurrent infections [74].

lowed by chronic inﬂammation of the gut and lungs.

Furthermore, asymptomatic carriers of the defective Concluding remarks

genes are reported to have an increased incidence of Emerging information on the genetic basis of various dis-

discoid lupus [64]. eases has facilitated a better appreciation of the diverse

Defects in recombinase activation genes (RAG) have effects that genetic susceptibility defects can have on

been associated with severe combined immunodeﬁciency clinical disease phenotypes. In particular, recent ﬁndings

syndromes (SCID), yet a recent study reported hypo- on SLE immunopathogenesis have allowed us to better

morphic RAG mutations (resulting in 50% RAG activity) appreciate the association between autoimmune manifes-

in patients suffering from midline granulomatous disease tations and subtle immune system defects. Such immune

[65]. Midline granulomatous disease is an autoimmune defects, by virtue of not being critical enough to allow

disorder commonly observed in patients with granuloma- overwhelming infections to develop, seem to provide the

tosis with polyangiitis and NK or T cell lymphomas. In this perfect background for chronic inﬂammatory responses.

case also, although the complete absence of the gene Although no single pathogen has yet been associated with

product seems to be associated with profound immunode- SLE immunopathogenesis, recent data seem to converge

ﬁciency, autoimmune phenomena prevail in partial dele- towards the fact that chronic inﬂammation in SLE could

tion [66]. stem from the presence of chronic immune system activa-

Patients with Wiskott–Aldrich syndrome (WAS) lack tion towards an uncleared intruder.

the WAS protein (WASP), which is involved in regulation Apart from SLE, it seems that this link may also apply

of the actin cytoskeleton. Affected individuals present with to other autoimmune diseases such as T1DM, multiple

eczema, autoimmune manifestations, recurrent bacterial sclerosis (MS), rheumatoid arthritis (RA), IBD and Sjo¨g-

infections and lymphoma [67]. Both antibody production ren’s syndrome. Genetic studies have conﬁrmed that poly-

and cellular immune defects are observed in these patients morphisms within an interferon inducible gene, IRF5, are

and predispose individuals to chronic inﬂammation. Inter- linked to a predisposition to not only SLE, but also MS, RA,

estingly, malignancy develops primarily in patients with IBD and Sjo¨gren’s syndrome [72]. T1DM has also been

autoimmune manifestations [68]. linked to an IFN signature similar to the one observed in

Autoimmune polyendocrinopathy–candidiasis–ectoder- SLE, and polymorphisms of MDA5 (a gene encoding a

mal dystrophy (APECED) is another example in which cytosolic nucleic acid receptor) are associated with predis-

autoimmunity and infections coexist. Although generally position to T1DM in genome-wide association studies

considered a disease of immune regulation dysfunction [75,76]. Finally, high numbers of EBV-infected B cells

with organ-speciﬁc autoimmune manifestations (e.g. hy- are observed in tertiary lymphoid tissues of the central

poparathyroidism and adrenocortical failure), chronic mu- nervous system in MS patients [77]. Thus, it seems that

cocutaneous candidiasis is also invariably present [69]. different autoimmune diseases might share common mo-

Although current concepts support the existence of regu- lecular defects and could share the same pattern of immu-

latory pathway defects in this disease, a plausible expla- nodeﬁciency that leads to the chronic infection and

nation for the fact that infections are also commonly immune hyper-reactivity proposed above.

observed in these patients is still missing. We have presented information that suggests overlap-

IgA deﬁciency is the most common type of primary ping features between systemic autoimmunity and immu-

immunodeﬁciency and although it can exist undiagnosed, nodeﬁciency. Patients with SLE develop infections

it is associated with the development of autoimmune and because of defects in elements of the immune response.

atopic phenomena in a substantial number of patients. Similarly, patients with immunodeﬁciency present with

Unaffected relatives of IgA-deﬁcient patients also have a autoimmune manifestations. In states of immunodeﬁcien-

higher prevalence for autoimmune manifestations com- cy, defects in immune response genes lead to uncleared

pared with the general population [70]. What is even infections and autoimmunity, whereas in systemic auto-

more interesting is that IgA deﬁciency is frequently immunity, subtle defects of immune response genes lead

found in patients previously diagnosed with autoimmune both directly to autoimmunity and indirectly by failure to

diseases such as SLE (1–5.2%) and rheumatoid arthritis clear pathogens, whose presence ampliﬁes the autoim-

(2–4.7%) [71]. mune process (Figure 2). Although autoimmunity and

CVID patients display low IgG and IgM levels and immunodeﬁciency occupy distinct chapters in textbooks,

decreased antibody responses to common infectious agents it appears that they are inextricably interconnected and

106

Review Trends in Molecular Medicine February 2012, Vol. 18, No. 2

20 Iliopoulos, A.G. and Tsokos, G.C. (1996) Immunopathogenesis and

Autoimmunity Immunodeficiency spectrum of infections in systemic lupus erythematosus. Semin.

Subclinical infections and Severe infections and Arthritis Rheum. 25, 318–336

autoimmunity autoimmunity 21 Patole, P.S. et al. (2005) Viral double-stranded RNA aggravates lupus

nephritis through Toll-like receptor 3 on glomerular mesangial cells

and antigen-presenting cells. J. Am. Soc. Nephrol. 16, 1326–1338

22 Feng, X. et al. (2006) Association of increased interferon-inducible gene

Low Sever ity of immune defect High

expression with disease activity and lupus nephritis in patients with

TRENDS in Molecular Medicine systemic lupus erythematosus. Arthritis Rheum. 54, 2951–2962

23 Tucci, M. et al. (2008) Glomerular accumulation of plasmacytoid

Figure 2. Scale of the severity of immune system-related genetic defects.

dendritic cells in active lupus nephritis: role of interleukin-18.

Milder genetic defects may result in multiple subclinical infections and the

Arthritis Rheum. 58, 251–262

development of an autoimmunity-based phenotype. More severe genetic defects

24 Farkas, L. et al. (2001) Plasmacytoid dendritic cells (natural interferon-

may manifest as the presence of frequent and/or severe infections and a more

immunodeficiency-oriented phenotype. alpha/beta-producing cells) accumulate in cutaneous lupus

erythematosus lesions. Am. J. Pathol. 159, 237–243

25 Crawford, D.H. et al. (2002) Sexual history and Epstein–Barr virus

infection. J. Infect. Dis. 186, 731–736

one should be always considered in the presence of the 26 Gross, A.J. et al. (2005) EBV and systemic lupus erythematosus: a new

other. perspective. J. Immunol. 174, 6599–6607

27 James, J.A. et al. (1997) An increased prevalence of Epstein–Barr virus

infection in young patients suggests a possible etiology for systemic

Disclosure statement lupus erythematosus. J. Clin. Invest. 100, 3019–3026

28 Berner, B.R. et al. (2005) Phenotypic and functional analysis of EBV-

The authors have no conﬂicts of interest.

speciﬁc memory CD8 cells in SLE. Cell Immunol. 235, 29–38

29 Rezaei, N. et al. (2011) X-linked lymphoproliferative syndrome: a

References genetic condition typiﬁed by the triad of infection, immunodeﬁciency

1 Tsokos, G.C. (2011) Systemic lupus erythematosus. N. Engl. J. Med. and lymphoma. Br. J. Haematol. 152, 13–30

365, 2110–2121 30 Detre, C. et al. (2010) SLAM family receptors and the SLAM-associated

2 Crispin, J.C. et al. (2010) Pathogenesis of human systemic lupus protein (SAP) modulate T cell functions. Semin. Immunopathol. 32,

erythematosus: recent advances. Trends Mol. Med. 16, 47–57 157–171

3 Cunninghame Graham, D.S. (2009) Genome-wide association studies 31 Aslanidis, S. et al. (2008) Parvovirus B19 infection and systemic lupus

in systemic lupus erythematosus: a perspective. Arthritis Res. Ther. 11, erythematosus: activation of an aberrant pathway? Eur. J. Intern. Med.

119 19, 314–318

4 Sellam, J. et al. (2007) Decreased B cell activating factor receptor 32 Puliaeva, I. et al. (2009) Therapeutic potential of CD8 cytotoxic T

expression on peripheral lymphocytes associated with increased lymphocytes in SLE. Autoimmun. Rev. 8, 219–223

disease activity in primary Sjogren’s syndrome and systemic lupus 33 Peng, S.L. et al. (1998) Perforin protects against autoimmunity in

erythematosus. Ann. Rheum. Dis. 66, 790–797 lupus-prone mice. J. Immunol. 160, 652–660

5 Warnatz, K. et al. (2009) B-cell activating factor receptor deﬁciency is 34 Herman, T.E. and Siegel, M.J. (2010) Familial hemophagocytic

associated with an adult-onset antibody deﬁciency syndrome in lymphohistiocytosis. J. Perinatol. 30, 363–365

humans. Proc. Natl. Acad. Sci. U.S.A. 106, 13945–13950 35 Kang, I. et al. (2004) Defective control of latent Epstein–Barr virus

6 Alcais, A. et al. (2009) Human genetics of infectious diseases: between infection in systemic lupus erythematosus. J. Immunol. 172, 1287–1294

proof of principle and paradigm. J. Clin. Invest. 119, 2506–2514 36 Holvast, A. et al. (2009) Studies of cell-mediated immune responses to

7 Grammatikos, A.P. (2008) The genetic and environmental basis of inﬂuenza vaccination in systemic lupus erythematosus. Arthritis

atopic diseases. Ann. Med. 40, 482–495 Rheum. 60, 2438–2447

8 Tsokos, G.C. and Fleming, S.D. (2004) Autoimmunity, complement 37 Crispin, J.C. et al. (2008) How signaling and gene transcription

activation, tissue injury and reciprocal effects. Curr. Dir. Autoimmun. aberrations dictate the systemic lupus erythematosus T cell

7, 149–164 phenotype. Trends Immunol. 29, 110–115

9 Zhang, S.Y. et al. (2007) TLR3 deﬁciency in patients with herpes 38 Lieberman, L.A. and Tsokos, G.C. (2010) The IL-2 defect in systemic

simplex encephalitis. Science 317, 1522–1527 lupus erythematosus disease has an expansive effect on host

10 von Bernuth, H. et al. (2008) Pyogenic bacterial infections in humans immunity. J. Biomed. Biotechnol. 2010, 740619

with MyD88 deﬁciency. Science 321, 691–696 39 Park, H.B. et al. (2004) Association of reduced CD4 T cell responses

11 Moser, K.L. et al. (2009) Recent insights into the genetic basis of speciﬁc to varicella zoster virus with high incidence of herpes zoster in

systemic lupus erythematosus. Genes Immun. 10, 373–379 patients with systemic lupus erythematosus. J. Rheumatol. 31, 2151–

12 Hewagama, A. and Richardson, B. (2009) The genetics and epigenetics 2155

of autoimmune diseases. J. Autoimmun. 33, 3–11 40 Dhir, V. et al. (2009) Increased T-lymphocyte apoptosis in lupus correlates

13 Doria, A. et al. (2008) Infections as triggers and complications of with disease activity and may be responsible for reduced T-cell frequency:

systemic lupus erythematosus. Autoimmun. Rev. 8, 24–28 a cross-sectional and longitudinal study. Lupus 18, 785–791

14 Deng, G.M. and Tsokos, G.C. (2008) Cholera toxin B accelerates disease 41 Holst, J. et al. (2008) Scalable signaling mediated by T cell antigen

progression in lupus-prone mice by promoting lipid raft aggregation. J. receptor-CD3 ITAMs ensures effective negative selection and prevents

Immunol. 181, 4019–4026 autoimmunity. Nat. Immunol. 9, 658–666

15 Poole, B.D. et al. (2009) Aberrant Epstein–Barr viral infection in 42 Cope, A.P. (2004) Altered signalling thresholds in T lymphocytes cause

systemic lupus erythematosus. Autoimmun. Rev. 8, 337–342 autoimmune arthritis. Arthritis Res. Ther. 6, 112–116

16 Hakkim, A. et al. (2010) Impairment of neutrophil extracellular trap 43 Yoshitomi, H. et al. (2005) A role for fungal b-glucans and their receptor

degradation is associated with lupus nephritis. Proc. Natl. Acad. Sci. Dectin-1 in the induction of autoimmune arthritis in genetically

U.S.A. 107, 9813–9818 susceptible mice. J. Exp. Med. 201, 949–960

17 Villanueva, E. et al. (2011) Netting neutrophils induce endothelial 44 Huang, Z. et al. (2011) Involvement of CD226 NK cells in

damage, inﬁltrate tissues, and expose immunostimulatory molecules immunopathogenesis of systemic lupus erythematosus. J. Immunol.

in systemic lupus erythematosus. J. Immunol. 187, 538–552 186, 3421–3431

18 Garcia-Romo, G.S. et al. (2011) Netting neutrophils are major inducers 45 Arason, G.J. et al. (2010) Primary immunodeﬁciency and autoimmunity:

of type I IFN production in pediatric systemic lupus erythematosus. lessons from human diseases. Scand. J. Immunol. 71, 317–328

Sci. Transl. Med. 3, 73ra20 46 Ochonisky, S. et al. (1993) Acquired C1 inhibitor deﬁciency revealing

19 Heinlen, L.D. et al. (2007) Clinical criteria for systemic lupus systemic lupus erythematosus. Dermatology 186, 261–263

erythematosus precede diagnosis, and associated autoantibodies are 47 Chen, M. et al. (2010) The complement system in systemic autoimmune

present before clinical symptoms. Arthritis Rheum. 56, 2344–2351 disease. J. Autoimmun. 34, J276–J286

107

Review Trends in Molecular Medicine February 2012, Vol. 18, No. 2

48 Isaak, A. et al. (2008) Physiological up-regulation of inhibitory 67 Notarangelo, L.D. et al. (2008) Wiskott–Aldrich syndrome. Curr. Opin.

receptors Fc gamma RII and CR1 on memory B cells is lacking in Hematol. 15, 30–36

SLE patients. Int. Immunol. 20, 185–192 68 Sullivan, K.E. et al. (1994) A multiinstitutional survey of the Wiskott–

49 Deng, Y. and Tsao, B.P. (2010) Genetic susceptibility to systemic lupus Aldrich syndrome. J. Pediatr. 125, 876–885

erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683–692 69 Lankisch, T.O. et al. (2009) The autoimmune polyendocrinopathy–

50 Dommett, R.M. et al. (2006) Mannose-binding lectin in innate candidiasis–ectodermal dystrophy or autoimmune polyglandular

immunity: past, present and future. Tissue Antigens 68, 193–209 syndrome type 1. Semin. Liver Dis. 29, 307–314

51 Chaussabel, D. et al. (2008) A modular analysis framework for blood 70 Jorgensen, G.H. et al. (2009) Familial aggregation of IgAD and

genomics studies: application to systemic lupus erythematosus. autoimmunity. Clin. Immunol. 131, 233–239

Immunity 29, 150–164 71 Jacob, C.M. et al. (2008) Autoimmunity in IgA deﬁciency: revisiting the

52 Villa-Forte, A. et al. (2008) HLA class I deﬁciency syndrome mimicking role of IgA as a silent housekeeper. J. Clin. Immunol. 28 (Suppl. 1),

Wegener’s granulomatosis. Arthritis Rheum. 58, 2579–2582 S56–S61

53 Chan, O.T. et al. (2001) Deﬁciency in beta2-microglobulin, but not CD1, 72 Bonilla, F.A. and Geha, R.S. (2009) Common variable immunodeﬁciency.

accelerates spontaneous lupus skin disease while inhibiting nephritis Pediatr. Res. 65, 13R–19R

lpr

in MRL-Fas mice: an example of disease regulation at the organ 73 Cunningham-Rundles, C. and Bodian, C. (1999) Common variable

level. J. Immunol. 167, 2985–2990 immunodeﬁciency: clinical and immunological features of 248

54 McKinney, E.F. et al. (2010) A CD8 T cell transcription signature patients. Clin. Immunol. 92, 34–48

predicts prognosis in autoimmune disease. Nat. Med. 16, 586–591 74 Howard, V. et al. (2006) The health status and quality of life of adults

55 Khan, S. et al. (2011) Do ribosomopathies explain some cases of with X-linked agammaglobulinemia. Clin. Immunol. 118, 201–208

common variable immunodeﬁciency? Clin. Exp. Immunol. 163, 96–103 75 Concannon, P. et al. (2008) A human type 1 diabetes susceptibility locus

56 Odendahl, M. et al. (2000) Disturbed peripheral B lymphocyte maps to chromosome 21q22.3. Diabetes 57, 2858–2861

homeostasis in systemic lupus erythematosus. J. Immunol. 165, 76 Nejentsev, S. et al. (2009) Rare variants of IFIH1, a gene implicated in

5970–5979 antiviral responses, protect against type 1 diabetes. Science 324, 387–

57 Kuan, A.P. et al. (2000) Immunoglobulin isotype determines 389

pathogenicity in antibody-mediated myocarditis in naive mice. Circ. 77 Seraﬁni, B. et al. (2007) Dysregulated Epstein–Barr virus infection in

Res. 86, 281–285 the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912

58 Chan, O.T. et al. (1999) A novel mouse with B cells but lacking serum 78 Poole, B.D. et al. (2006) Epstein–Barr virus and molecular mimicry in

antibody reveals an antibody-independent role for B cells in murine systemic lupus erythematosus. Autoimmunity 39, 63–70

lupus. J. Exp. Med. 189, 1639–1648 79 Vanderlugt, C.L. and Miller, S.D. (2002) Epitope spreading in immune-

59 Torres-Salido, M. et al. (2011) Systemic lupus erythematosus as a ﬁrst mediated diseases: implications for immunotherapy. Nat. Rev.

presentation of common variable immunodeﬁciency associated with Immunol. 2, 85–95

infrequent mannose-binding lectin gene polymorphisms. Rheumatol. 80 Arbuckle, M.R. et al. (2003) Development of autoantibodies before the

Int. 31, 537–541 clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349,

60 Yong, P.F. et al. (2008) Management of hypogammaglobulinaemia 1526–1533

occurring in patients with systemic lupus erythematosus. 81 Munz, C. et al. (2009) Antiviral immune responses: triggers of or

Rheumatology (Oxford) 47, 1400–1405 triggered by autoimmunity? Nat. Rev. Immunol. 9, 246–258

61 Skare, T.L. et al. (2010) Serum IgA deﬁciency in systemic lupus 82 Stow, N.W. et al. (2010) Superantigens. Otolaryngol. Clin. North Am.

erythematosus. Acta Reumatol. Port. 35, 273–274 43, 489–502

62 Katsiari, C.G. et al. (2010) The pathophysiologic role of monocytes and 83 Wucherpfennig, K.W. (2001) Mechanisms for the induction of

macrophages in systemic lupus erythematosus: a reappraisal. Semin. autoimmunity by infectious agents. J. Clin. Invest 108, 1097–1104

Arthritis Rheum. 39, 491–503 84 Zipris, D. et al. (2005) TLR activation synergizes with Kilham rat virus

63 Monrad, S.U. et al. (2008) Myeloid dendritic cells display infection to induce diabetes in BBDR rats. J. Immunol. 174, 131–142

downregulation of C-type lectin receptors and aberrant lectin 85 Boyman, O. (2010) Bystander activation of CD4 T cells. Eur. J.

uptake in systemic lupus erythematosus. Arthritis Res. Ther. 10, R114 Immunol. 40, 936–939

64 Holland, S.M. (2010) Chronic granulomatous disease. Clin. Rev. 86 Stetson, D.B. (2009) Connections between antiviral defense and

Allergy Immunol. 38, 3–10 autoimmunity. Curr. Opin. Immunol. 21, 244–250

65 De Ravin, S.S. et al. (2010) Hypomorphic Rag mutations can cause 87 Kawai, T. and Akira, S. (2011) Toll-like receptors and their crosstalk

destructive midline granulomatous disease. Blood 116, 1263–1271 with other innate receptors in infection and immunity. Immunity 34,

66 Walter, J.E. et al. (2010) Expansion of immunoglobulin-secreting cells 637–650

and defects in B cell tolerance in Rag-dependent immunodeﬁciency. J. 88 Wilkins, C. and Gale, M., Jr (2010) Recognition of viruses by

Exp. Med. 207, 1541–1554 cytoplasmic sensors. Curr. Opin. Immunol. 22, 41–47

108