Autoimmunity and Immunodeficiency
Amrita Dosanjh, MD*
AUTHOR DISCLOSURE Dr. Dosanjh has
disclosed no financial relationships relevant to
this article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
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*Department of Pediatrics, Rady Childrens Hospital, San Diego, CA.
Education Gaps
Physicians may be unaware of the clinical manifestations of autoimmune
disease among patients with known primary immunodeficiencies.
Objectives After completing the article, the reader should be able to:
1. Describe the association between immunodeficiency and autoimmune
disease.
2. Describe the various types of autoimmune diseases associated with
immunodeficiency.
3. Recognize the clinical features of each of the primary immunodeficiencies
described.
4. Delineate the key molecular and cellular causes of autoimmune disease
among patients with primary immunodeficiency.
INTRODUCTION
Autoimmunity results from the production of functional and pathogenic autoanti-
bodies against target organs. The subsequent inflammation, degeneration, tissue
injury, and end-organ failure in the setting of primary immunodeficiency (PID)
exacerbates the course of PID. Multiple systems may be affected, including
vascular, joint, skin, endocrine, muscular, and circulating blood cells. Preliminary
screening for signs of autoimmune disease in the patient with PID can include
hemolytic anemia, markers for inflammation, and the presence of circulating
autoantibodies (eg, rheumatoid factor and antinuclear antibody). The connection
between immunodeficiency and autoimmunity is well recognized among pedi-
atric immune disorders. Autoimmune manifestations represent the second most
common clinical consequence of PID; recurrent infections remain the most
common. Advances in understanding the molecular and cellular biology of
disease have led to greater comprehension of the pathogenesis of these autoim-
mune disorders.
PID comprises a group of clinical diseases with a variety of underlying
genetic and molecular mechanisms. There are more than 150 PID diseases,
and PID leads to increased susceptibility to infection. Most of the PIDs present
with only B-cell defects (Fig 1). The types of infections that occur in the child
with a PID can help establish the immune profile of the patient and narrow the
Vol. 36 No. 11 NOVEMBER 2015 489
 differential diagnosis. Patients with defective cellular immu-
nity, such as in Omenn syndrome and severe combined
immunodeficiency syndrome (SCID), are susceptible to
a wide variety of organisms, including fungi. In contrast,
patients with immunoglobulin (Ig)A deficiency have
a comparatively mild presentation of localized bacterial
illness, such as recurrent sinusitis, and some patients
have minimal to no symptoms. No matter the presenta-
tion, all PIDs have been associated with autoimmune
disorders.
Autoimmunity in pediatric patients with PID is believed
to be due to a variety of possible underlying mechanisms.
These include:
• Secondary lymphopenia, which permits proliferation
and expansion of autoreactive lymphocytic clones.
• Defects of immune tolerance, the state of unre-
sponsiveness to agents that otherwise would elicit an
immune response. The defects may occur in the
central organs involved in immune defense such as
the thymus and bone marrow or in the peripheral
lymph nodes and organs.
• Defects in apoptosis/clearance of apoptotic bodies/
cellular debris.
• Immunoproliferation.
• Defects in signaling pathways.
• Defects in innate cellular mechanisms.
This review summarizes the clinical pathogenesis, diag-
nosis, and management of patients with pediatric PID and
autoimmunity. This topic is very complex and this review is
Figure 1. B-cell defects, either as isolated or combined defects, account
for most cases of primary immunodeficiency.
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intended to provide the clinician with an overview of PID
and autoimmune disease to improve early recognition and
treatment of these entities. Figure 2 illustrates the innate
and adaptive immune systems and the cells involved in
defective responses to antigen.
DEFECTS IN MUCOSAL IMMUNITY
IgA deficiency is one of the more common primary humoral
immunodeficiencies, affecting as many as 1 in 333 white
patients. Some present only with gastrointestinal or sino-
pulmonary infections; others develop autoimmune disease.
Many patients have auto-IgA antibodies and can develop
a wide variety of autoimmune diseases, including rheuma-
toid disease, systemic lupus erythematosus (SLE), biliary
and hepatic disease, and diabetes. A more common auto-
immune disease association with IgA deficiency is celiac
disease. As many as 1 in 200 patients with celiac disease may
have IgA deficiency. The mechanism of autoimmunity in
IgA deficiency is believed to involve impaired clearance of
cellular debris/apoptotic bodies, but this is still a subject of
investigation.
The characteristic diagnostic features of IgA deficiency
include low IgA concentrations for age with normal IgG
values and T-cell numbers and function. Because affected
patients have normal cellular function, normal serum IgG
concentrations, and generally mild clinical presentations,
management focuses on treatment and prevention of in-
fections via the judicious use of antibiotics. Replacement
strategies such as intravenous immunoglobulin (IVIg) are
not usually part of the management. Transfusion reactions
in patients with IgA deficiency can be severe and life-
threatening because a significant portion of affected
patients develops antibodies against IgA. The exact inci-
dence of anti-IgA-mediated blood transfusion reactions
has not been established.
DEFECTS OF SIGNALING PATHWAYS
Wiskott Aldrich Syndrome
Wiskott Aldrich syndrome (WAS) is an example of a primary
immunodeficiency syndrome with an underlying signaling
pathway defect that results in progressive, defective
responses to bacterial and viral infections. WAS is an
X-linked immunodeficiency characterized by significantly
increased risk for autoimmune disease in addition to recur-
rent infections, eczema, thrombocytopenia, and abnormal
lymphocyte function. The estimated frequency is between 1
and 10 million males, and the underlying genetic defect is in
Figure 2. A Venn diagram showing cell types
in innate and adaptive immunity.
the WAS gene, which encodes for a multidomain protein
(WASp).
WASp is a regulatory protein that has a key role in
signaling from the cell surface to the actin cytoskeleton.
WASp is integral to the regulation of cytoskeletal organi-
zation in hematopoietic cells. The gene is located on the X
chromosome and encodes a 502-amino acid protein, which
is produced normally in unaffected children. Mutations in
the WAS gene results in B cells that are hyperresponsive to
B-cell and toll-like receptors. The underlying mechanisms of
autoimmune disease in association with WAS are varied
and include impaired signaling pathways, cytokine produc-
tion, apoptosis, and clearance. Stem cell transplantation
remains the most effective therapy in WAS.
The autoimmune disease associated with WAS affects
multiple systems in an estimated 25% to 70% of patients. The
presentations of autoimmune diseases include cytopenias,
arthritis, vasculitis, and renal disease. The most common
autoimmune manifestation is hemolytic anemia, followed
by arthritis and neutropenia. The autoimmune disease
tends to present early in life and is associated with a lack
of therapeutic response. Those patients with autoimmune
disease have a worse prognosis than patients who do not
develop autoimmune disease.
Hyper-IgE Syndrome (HIES)
HIES is a primary immunodeficiency that typically
presents with recurrent skin abscesses, eczema, eosino-
philia, and extreme elevations in serum IgE concentra-
tions. Genetic transmission can be autosomal dominant or
autosomal recessive. The hallmark pulmonary findings are
recurrent pneumonia with pneumatocele formation. Pa-
tients who have autosomal recessive HIES are especially
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prone to autoimmune disease. Unlike those with auto-
somal dominant disease, patients with autosomal reces-
sive disease do not exhibit the classic skeletal and dental
malformations associated with HIES. Autoimmune clinical
findings encompass a variety of autoimmune diseases, such
as idiopathic thrombocytopenic purpura, SLE, and nephritic
syndromes. One of the signaling pathways that is dys-
regulated in this disease is the STAT5 pathway due to IgE
binding to a STAT5 high-affinity receptor. STAT5b is a uni-
versal transcription factor that plays a pivotal role in the
development of a number of diseases, including autoim-
mune and allergic diseases. STAT5b-deficient patients have
decreased numbers of regulatory CD4þCD25 T regulatory
(Treg) cells. Deficiency of STAT5b can present clinically with
autoimmune arthritis, thyroiditis, thrombocytic purpura, and
lymphopenia.
DEFECTS IN TOLERANCE
Immunodysregulation, Polyendocrinopathy,
Enteropathy, X-linked (IPEX) Syndrome
IPEX syndrome is a rare disease whose incidence is increas-
ing, suggesting that it may have been underrecognized in
the past. Approximately 136 patients with 63 FOXP3 muta-
tions have been identified. A triad of symptoms identified as
hallmarks of the disease are intractable diarrhea, diabetes,
and eczema. IPEX syndrome can be fatal in early life and
often presents with recurrent diarrhea or type 1 diabetes
mellitus. Autoimmune manifestations include cytopenias,
hepatitis, hypothyroidism, arthritis, and alopecia. Infants
often appear normal at birth, only to decline rapidly in the
first few postnatal months. The autoimmune enteropathy,
which is characteristic of IPEX syndrome, can worsen when
Vol. 36 No. 11 NOVEMBER 2015 491
 formula is introduced in an affected infant’s diet. The
association with early-onset diabetes can present either
before or after enteritis, and the diabetes is difficult to
control. Most cases of type 1 diabetes are identified by
autoantibodies and immune-mediated damage of the pan-
creas found on histologic analysis. The cellular immune
defects leading to autoimmune disease include a decreased
number of Treg cells, abnormal responses of CD4 T cells,
and aberrant autoantibody production.
Due to the protein-losing enteropathy, serum concentra-
tions of IgG, IgA, and IgM are low, but IgE values are
markedly elevated. There are no specific diagnostic tests
or single pathognomonic feature of IPEX syndrome. Treat-
ment involves supportive care, immunosuppression, and
hematopoietic stem cell transplantation.
Common Variable Immunodeficiency (CVID)
CVID is a broad collection of PIDs characterized by reduced
serum concentrations of IgG, IgA, or IgM. The serum IgG
value is always markedly reduced. The prevalence is esti-
mated to be 1 in 25,000 to 50,000. Most cases occur sporad-
ically, although familial inheritance has been reported, and
most patients are diagnosed between the ages of 20 and
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40 years. CVID is difficult to diagnose before age 4 years,
when serum concentrations of IgG are better established. The
condition is heterogeneous in its presentation and diagnostic
findings, although autoimmune disease is an associated
finding in approximately 20% of patients. CVID autoimmune
complications include rheumatoid arthritis, diabetes, inflam-
matory bowel disease, and SLE. In a subset of patients, anti-
IgA, antiphospholipid, and anticardiolipin antibodies
develop. The underlying immune mechanisms include
decreased switched memory B cells and proliferation of
autoreactive B cells, aberrant cytokine production, and
decreased Treg cell populations.
X-linked Agammaglobulinemia (XLA)
XLA is caused by a mutation in the Bruton tyrosine kinase
(BTK) gene on the X chromosome. The disease affects
primarily B-cell number and function, with T-cell numbers
and function generally remaining preserved. The autoim-
mune presentations include arthritis, alopecia, inflamma-
tory bowel disease, anemia, and scleroderma. Diagnostic
testing shows low or absent concentrations of all of the
major immunoglobulins (IgG, IgA, and IgM). The CD4 and
CD8 populations are preserved and CD19/20 lymphocyte
Figure 3. The complement cascade.
populations are diminished. One of the mechanisms of
autoimmune disease is the proliferation of autoreactive
B cells.
DEFECTS IN T-CELL AND B-CELL DEVELOPMENT AND
PROLIFERATION
Omenn and DiGeorge Syndromes
Omenn and DiGeorge syndromes are PIDs that involve
defects in cellular growth and survival. Omenn syndrome
has an autosomal recessive inheritance, and DiGeorge
syndrome is an autosomal dominant condition.
Omenn syndrome is caused primarily by mutations in
RA1 or RAG2, two enzymes necessary for T-cell and B-cell
receptor arrangement. Autoimmune characteristics include
dermatitis, enteritis, and hepatitis. Autoimmunity is be-
lieved to result from expansion of autoreactive T cells and
decreased Treg cell production.
DiGeorge syndrome is an autosomal dominant condition
resulting in defective development of the thymus, para-
thyroid, and heart due, in most cases, to a chromosome
22q11 deletion. Associated autoimmune diseases are hema-
tologic conditions such as cytopenias and anemia, arthritis,
vitiligo, psoriasis, and thyroiditis. The failure in T-cell devel-
opment that results in autoreactive T cells and formation of
autoantibodies causes tissue injury.
Severe Combined Immunodeficiency
SCID is a primary immune deficiency with severe defects
in both T and B cells. When discovered in a patient, SCID is
a medical emergency; stem cell transplantation can suc-
cessfully extend life when performed early in the disease
course. Although affected infants appear normal at birth,
they have no functional T lymphocytes, which results in
susceptibility to severe infections. Autoimmune disease is
associated with SCID due to both defective central toler-
ance (reduced autoimmune regulator AIRE in the thymus)
and peripheral tolerance (eg, reduced numbers of Treg
cells).
with SLE in 1 in 20 to 100,000 patients. In one study of
40 patients with C1q deficiency, 10 had evidence of SLE.
An estimated 90% of homozygous C1q-deficient patients
develop SLE. Anti-C1q antibodies may be used clinically as
a marker for lupus nephritis. Among C2-deficient patients,
10% to 30% may develop SLE. These associations lend
support to the role of complement in clearing immune
complexes and with complement deficiency, the subsequent
development of autoimmune disease. Another possible
mechanism is that apoptotic bodies are a source of lupus
self-antigen, and failure to remove them could lead to au-
toantibody production. The innate immune system may be
protective against lupus by negative selection of B cells. In
a case study of a 10-year-old girl with both hyper-IgM and
C1q deficiency, SLE developed without evidence of renal
involvement. The authors suggested that elevated concen-
trations of IgM might be protective.
TREATMENT OF AUTOIMMUNE DISEASE IN PRIMARY
IMMUNODEFICIENCY DISORDERS
IVIg may be used to modulate the immune system in
autoimmune disease. IVIg may expand and enhance the
function of FOXP3-positive Treg cells. In those who have
XLA, IVIg may lead to a partial correction of the underlying
defect. Stem cell transplantation has been successful in
patients with PID who have a poor prognosis and do not
respond to IVIg. Patients who have SCID and WAS have
been successfully treated with stem cell transplantation.

COMPLEMENT DEFICIENCIES AUTOIMMUNE DISEASE

The complement system plays a major role in defense

against infections. The pathways of complement activation
and factors are illustrated in Figure 3. Laboratory screen-
ing tests for CH50, C3, C4, and AP50 can diagnose most
complement defects. The association with autoimmune
disorders may be related to defective clearance of immune
complexes as a result of low concentrations of complement. Figure 4. A Venn diagram showing overlap among immunodeficiency,
C2 deficiency, inherited in a recessive pattern, is associated autoimmune disease and rheumatic disease.

Vol. 36 No. 11 NOVEMBER 2015 493

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 Future strategies may include B-cell-based treatments of
Th-17-related autoimmune inflammation.
CONCLUSIONS
PIDs comprise a diverse group of clinical and genetic
disorders that result in susceptibility to infection. A subset
of affected patients develop autoimmune disease (Fig 4).
The reasons for an association between PID and autoim-
mune disease are being studied and currently include:
• Secondary lymphopenia that permits proliferation,
expansion, and autoreactive lymphocytic clones
• Defects of tolerance
• Defects in apoptosis/clearance
• Immunoproliferation
• Defects in signaling pathways
• Defects in innate cellular mechanisms
Patients with PID have distinct clinical features, genetic
transmission patterns, microorganism susceptibilities, and
ages of onset.
Early recognition of the signature patterns in each PID,
together with diagnostic testing, can lead to earlier diagnosis
and treatment of the pediatric patient with immunodefi-
ciency and associated autoimmune disease.
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Summary
The references provided include data from evidence A and B studies
based on the relevant populations. Because many primary
immunodeficiencies associated with autoimmune diseases are rare,
illustrative cases (evidence D) also are referenced.
• On the basis of level A evidence, immunoglobulin A
deficiency is the most common primary immunodeficiency
and is associated with defective mucosal immunity and
autoimmune disease.
• On the basis of strong evidence (level A), Wiskott Aldrich
syndrome presents early in life and is associated with
autoimmune arthritis and anemia.
• On the basis of strong evidence in the literature, a number of
primary immunodeficiencies are associated with defects in
T regulatory cell number and development, cytokine
aberrancies, and, as a consequence, production of
autoantibodies.
• On the basis of strong evidence (level A) and case reports
(level D), complement deficiency can be associated with
autoimmune disease, most notably systemic lupus
erythematosus.
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 Autoimmunity and Immunodeficiency
Amrita Dosanjh
Pediatrics in Review 2015;36;489
DOI: 10.1542/pir.36-11-489

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 Autoimmunity and Immunodeficiency
Amrita Dosanjh
Pediatrics in Review 2015;36;489
DOI: 10.1542/pir.36-11-489

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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