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Autoantibody-Mediated Phenocopies of

Primary Immunodeficiency Diseases

Sarthak Gupta, Sarah K. Browne

Anticytokine autoantibodies have been identified in health and There are numerous commonalities and distinctions worth
disease, with their role in pathogenesis ranging from none to highlighting among anticytokine autoantibody–associated immune
directly causal. In fact, it is becoming increasingly recognized deficiency. Shared in common is the presence of high-titer, neutral-
that neutralizing, high-titer autoantibodies cause a variety of izing anticytokine autoantibodies of the immunoglobulin G (IgG)
potentially life-threatening illnesses. Their manifestations are isotype. PAP caused by anti–GM-CSF autoantibodies appears
diverse, and their clinical presentation is generally a reflection of to be primarily a lung disease largely resulting from disruption
the cytokine pathways that are rendered functionally deficient. of GM-CSF–dependent pulmonary surfactant catabolism. In
Examples include pulmonary alveolar proteinosis (PAP) vitro studies using primary human cells and mouse work have
caused by anti–granulocyte macrophage–colony-stimulating demonstrated that anti–GM-CSF autoantibodies cause immune
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factor (GM-CSF) autoantibodies ; disseminated nontuberculous dysfunction, largely through transcription factor PU.1, which
mycobacterial (NTM) and other opportunistic infections and may explain pulmonary and extrapulmonary infections observed
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anti–interferon-γ (IFN-γ) autoantibodies ; chronic mucocutaneous in PAP, particularly those opportunists known to be controlled
1
candidiasis (CMC) and anti–interleukin (IL)-17A, anti–IL-17F, by neutrophils or macrophages. PAP caused by anti–GM-CSF
3,4
or anti–IL-22 autoantibodies ; and staphylococcal skin infection autoantibodies is similar to severe immune deficiency caused
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and anti–IL-6 autoantibodies (Table 40.1). In each of these cases by anti-IFN-γ autoantibodies in that both diseases have adult
a high-titer, biologically active autoantibody has been identified onset. On the basis of broad screening for other autoantibodies,
in association with a unique clinical syndrome. Although this it appears they make high-titer neutralizing autoantibody against
list is not exhaustive, these diseases are of particular interest only one cytokine and do not demonstrate an increased frequency
1,2
in that the clinical manifestations are often similar to those in of other autoantibodies or forms of autoimmunity. Patients with
patients with genetic defects in the same cytokine-associated autoantibodies against IL-17A, IL-17F, IL-22, and CMC are differ-
pathways. The mendelian defects that confer a similar phenotype ent in that, so far, all have had an underlying primary diagnosis
to their anticytokine autoantibody counterpart also provide a of either autoimmune polyendocrinopathy with candidiasis and
3,4
strong biological rationale for establishing the autoantibodies as ectodermal dysplasia (APECED) or thymic neoplasia. Thus in
causal. Although a number of other anticytokine–autoantibody the case of APECED, a mendelian defect in the gene AIRE, which
associated syndromes such as pure red-cell aplasia (antierythro- is responsible for negative selection for autoreactive T cells in the
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poietin autoantibodies) and severe osteoporosis in celiac disease thymus, the onset of anticytokine autoantibodies and CMC occurs
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(antiosteoprotegerin autoantibodies) have been described, this earlier in life. Occasionally, CMC is the initial presentation of
chapter focuses on those that increase susceptibility to infection. thymoma (just as myasthenia gravis caused by antiacetylcholine
receptor autoantibodies must prompt evaluation for thymoma)
KEY CONCEPTS and highlights that for all anticytokine autoantibody–associated
Anticytokine Autoantibody–Associated Primary syndromes, the time line for development of anticytokine auto-
antibodies relative to the observation of clinical disease is largely
Immunodeficiency Diseases unknown. Additionally, patients with thymoma and APECED
can develop multiple anticytokine autoantibodies, although
• Anticytokine autoantibodies have been identified in a group of patients
with immunodeficiency diseases characterized by the development they have a proclivity for certain ones, including type I IFNs,
of high-titer, neutralizing autoantibodies to cytokines. IL-17A, IL-17F, IL-22, and, in the case of thymoma (but not
• The clinical manifestations in patients with anticytokine autoantibodies APECED), IL-12. Given the presence of multiple neutralizing
are similar to those seen in patients with genetic defects in the pathway autoantibodies, and the role of the thymus in T-cell development
of the target cytokine. that can lead to intrinsic T-cell defects that could also confer
• Immunodeficiency syndromes described include those associated with infection susceptibility, it is challenging to prove that a particular
anti– granulocyte macrophage–colony-stimulating factor (GM-CSF)
autoantibodies and pulmonary alveolar proteinosis (PAP); anti–interferon anticytokine autoantibody is the necessary and sufficient agent
(IFN)-γ autoantibodies and severe immunodeficiency; anti–interleukin of disease pathogenesis. In the case of anti–IL-6 autoantibodies,
(IL)-17A, anti–IL-17F, and anti–IL-22 autoantibodies and chronic high-titer, neutralizing anti–IL-6 IgG was demonstrated in one
mucocutaneous candidiasis (CMC); and anti–IL-6 autoantibodies and 11-month-old child with recurrent staphylococcal skin infections
staphylococcal skin infection. and low C-reactive protein-reactive protein (CRP), an IL-6–driven
• Management of these syndromes involves treating the consequences inflammatory marker. The opportunity to identify common
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of the autoantibody (e.g., infectious manifestations, lung disease) or
targeting the autoantibody itself. clinical features around this entity is limited, since other cases
have yet to be identified.
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