Clinical Information

Primary immunodeficiencies or inborn errors of immunity (IEI) were originally defined by an increased risk of infections. Now it is clear that these diseases can also present with autoimmunity, autoinflammation, atopy, lymphoproliferation or  malignancy, and infections are not always the leading cause of morbidity and mortality. This gene panel includes IEI with presentations characterized by autoimmunity. Examples of conditions where this gene panel is useful include immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and other regulatory T-cell (Treg) defects; autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED or APS-1); and lymphoproliferation, solid organ autoimmunity, recurrent infections associated with gain-of-function STAT3 defects.

The development of autoimmune diseases can be caused by the dysregulation of the immune system, leading to defects in regulatory mechanisms that normally control the immune response. Thymic selection is critical for T-cell development and includes positive and negative selection of the maturing T cells. The positive selection ensures that mature T cells can recognize antigen-presenting molecules and thus carry out their function, whereas the negative selection eliminates developing T cells that are strongly autoreactive, including T cells directed against tissue-restricted antigens. The autoimmune regulator (AIRE) is responsible for intrathymic presentation of tissue-restricted antigens that would otherwise not be expressed in the thymus, and their absence in the thymus would allow the development of autoreactive T cells against these tissue-restricted antigens. Variants in the AIRE gene cause APECED because the self-antigens are not properly expressed in the thymus.

IPEX syndrome is characterized by systemic autoimmunity presenting in infancy. It typically presents with the triad of enteropathy (watery diarrhea), endocrinopathy (eg, insulin-dependent diabetes mellitus), and eczematous dermatitis. IPEX is caused by defects in the transcription factor FOXP3, which is required for the development of regulatory T cells. The regulatory (suppressive) actions of Tregs control autoimmunity. Tregs have different suppressive mechanisms, including cell contact-mediated cytotoxicity, sequestration of interleukin (IL)-2, and cytokine-mediated inhibition. Defects in the genes encoding these suppressive cytokines and cytokine receptors (eg, IL-10, IL-10 receptor alpha and beta, or transforming growth factor-beta [TGF-beta]) also lead to autoimmune manifestations. Cell-to-cell contact of membrane-bound molecules, such as CTLA-4, can transmit an inhibitory signal. In the absence of the inhibitory signal, CTLA-4 deficiency can manifest with recurrent infections, inflammatory bowel disease, in addition to autoimmunity. Increased (gain) of function in STAT3 signaling also decreases Treg numbers and function, leading to recurrent infections, lymphoproliferation, and, mainly, solid organ autoimmunity, such as thyroiditis, insulin-dependent diabetes mellitus, as well as autoimmune cytopenias.