Immunodeficiency disorders can lead to the development of autoimmunity

In this article, I briefly describe immunodeficiency disorders that disturb immune regulation, which can lead to the development of autoimmunity.

Table of Contents

Deficiencies in T-cell tolerance lead to autoimmunity

The adaptive immune system recognizes and eliminates foreign antigens. It also has to recognize self-MHC proteins and suppress reactions to self-antigens in the host. The induction of tolerance in the thymus and the monitoring activities of regulatory T cells aid in carrying out these processes. Deficits in T-cell tolerance mechanisms result in the development of autoimmunity.

Autoimmune polyendocrinopathy

A person with a defect in the autoimmune regulatory gene AIRE suffers from a disease called autoimmune polyendocrinopathy. The patient also has to suffer from candidiasis and ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome-1(APS-1).

Medullary epithelial cells of the thymus express the AIRE protein. The protein acts as a transcriptional regulator to control expression of a wide array of tissue-restricted antigens. These peripheral tissue proteins, when properly expressed in the thymus, facilitate the negative selection of auto-reactive T cells before they can exit into the circulation and the generation of thymic regulatory T cells.

Individuals with less expression of AIRE lead to reduced levels of tissue-specific antigens in medullary thymic epithelial cells. This allows the escape of autoreactive T cells into the periphery, where they precipitate organ-specific autoimmunity. Patients suffering from APECED go through endocrine dysfunction, including hypoadrenalism, hyperparathyroidism, and hypothyroidism, along with persistent candidiasis. Autoimmune reactions target antigens in endocrine organs such as the adrenal cortex, gonads, and pancreatic beta cells. While autoantibodies against these tissues are also detected, they may arise due to tissue damage caused by pathogenic T cells.

Immune dysregulation

During negative selection, many T cells able to recognize self-antigens get destroyed in the thymus. However, one class of self-reactive CD4⁺ T cells with regulatory capacities survives and actively inhibits reactions to these self-antigens in the periphery.

The transcription factor FoxP3 acts as a master regulator and controls the development and function of these regulatory T cells. FoxP3 also helps differentiate naïve CD4⁺ T cells into T_REG cells in the periphery. Patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome have inherited a mutated FoxP3 gene. An individual with a mutated FoxP3 gene, lacks expression of this protein and is almost devoid of T_REG cells. When these regulatory T cells are absent in the periphery, autoreactive T cells that have escaped central tolerance in the thymus go unchecked. This leads to systemic autoimmune disease. Affected infants often die in the first two years of life due to immune destruction of the bowel, pancreas, thyroid, and skin.

CD25, the α chain of the IL-2 receptor required for high-affinity IL-2 binding. Patients with autosomal recessive mutations in CD25 suffer from the same symptoms of autoimmune disease. IL-2 enhances the functions of regulatory T cells and absence of the high affinity IL-2R interferes with peripheral self tolerance. Mutations in the co-inhibitory protein CTLA4 also lead to inhibition of function in regulatory T cells leading to autoimmunity.

Autoimmunity and other immunodeficiency disorders

Autoimmunity is commonly associated with various immunodeficiency disorders, highlighting different defects in immune response and regulation. Mutations that lead to a reduced number of lymphocytes often result in both autoimmunity and immunodeficiency. For instance, hypomorphic mutations in RAG and Artemis proteins permit limited immunoglobulin and TCR gene rearrangements, leading to a decreased number and diversity of B and T cells. The scarcity of B cells triggers an increase in the B-cell survival factor BAFF, which supports the survival of autoreactive immature and peripheral B cells.

In the thymus, limited TCR gene rearrangements disrupt T-cell development resulting in reduced AIRE expression. This leads to the survival of autoreactive cells, which enter the circulation.

Immunodeficiencies that lead to reduced clearance of immune complexes and apoptotic cells may also lead to autoimmunity. Deficiencies in complement components C1q, C1r/s, C2, or C4 show a risk for the autoimmune disease systemic lupus erythematosus (SLE). These early complement components are strong opsonins for immune complexes, apoptotic cells and some bacteria. Impaired clearance of immune complexes and apoptotic cell components increases the likelihood that nuclear self-antigens trigger IFN-α production, leading to the breakdown of self-tolerance in autoreactive B and T cells.

Conclusion

The induction of tolerance in the thymus and the monitoring activities of regulatory T cells aid in carrying out these processes. The deficiencies in T-cell tolerance mechanisms result in the development of autoimmunity.

An individual with a defect in the autoimmune regulatory gene AIRE suffers from a disease called autoimmune polyendocrinopathy (APECED). Patients suffering from APECED go through endocrine dysfunction, including hypoadrenalism, hyperparathyroidism, and hypothyroidism, along with persistent candidiasis.

The transcription factor FoxP3 acts as a master regulator and controls the development and function of regulatory T cells. Patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome have inherited a mutated FoxP3 gene. An individual with a mutated FoxP3 gene, lacks expression of this protein and is almost devoid of T_REG cells. In the absence of these regulatory T cells in the periphery, autoreactive T cells that have escaped central tolerance in the thymus go unchecked. This leads to systemic autoimmune disease.

Mutations leading to a reduced number of lymphocytes often result in both autoimmunity and immunodeficiency. Immunodeficiencies that cause less clearance of immune complexes and apoptotic cells may also lead to autoimmunity. Deficiencies in complement components C1q, C1r/s, C2, or C4 show a risk for the autoimmune disease systemic lupus erythematosus (SLE).