Several PIDs (most of which are T cell–related) can cause severe gut inflammation. The prototypic example is immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), characterized by a widespread inflammatory enteropathy, food intolerance, skin rashes, autoimmune cytopenias, and diabetes. The syndrome is caused by loss of-function mutations in the gene encoding the transcription factor FOXP3, which is required for the acquisition of effector function by regulatory T cells. In most cases of IPEX, CD4+CD25+ regulatory T cells are absent from the blood. This condition has a poor prognosis and requires aggressive immunosuppression. The only possible curative approach is allogeneic HSCT. IPEX-like syndromes that lack a FOXP3 mutation have also been described. In some cases, CD25 (IL-2 receptor α subunit) and CD122 (IL-2 receptor β subunit) deficiencies have been found. Defective IL-2 receptor expression also impairs regulatory cell expansion/function. This functional T-cell deficiency means that IL-2 receptor–deficient patients are also at increased risk of opportunistic infections. It is noteworthy that abnormalities in regulatory T cells have been described in other PID settings, such as in Omenn syndrome, STAT5b deficiency, STIM1 (Ca flux) deficiency, and WAS; these abnormalities may account (at least in part) for the occurrence of inflammation and autoimmunity. The autoimmune features observed in a small fraction of patients with DiGeorge’s syndrome may have the same cause. Severe, early-onset inflammatory gut disease has been described in patients with a deficiency in the IL-10 receptor or IL-10.

Dominant mutations in genes encoding the regulatory molecule CTLA-4, recessive mutations in the gene encoding LRBA (a molecule involved in recycling of CTLA-4), as well as dominant gain-of-function mutation of STAT3 cause a multifaceted lymphoproliferative and autoimmune syndrome, frequently involving inflammatory bowel dis ease that can be associated with hypogammaglobulinemia. Molecular diagnosis is required before adapted targeted therapies are undertaken. Gain-of-function mutation of IK2F1 (Ikaros) or BACH2 deficiency can also cause colitis with multiple autoimmune features.

A distinct autoimmune entity is observed in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, which is characterized by autosomal recessive inheritance. It consists of multiple autoimmune manifestations that can affect solid organs in general and endocrine glands in particular. Mild, chronic Candida infection is often associated with this syndrome. The condition is due to mutations in the autoimmune regulator (AIRE) gene and results in impaired thymic expression of self-antigens by medullary epithelial cells and impaired negative selection of self-reactive T cells that leads to autoimmune manifestations.

A combination of hypogammaglobulinemia, autoantibody production, cold-induced urticaria or skin granulomas, or autoinflammation has been reported and has been termed PLCγ2-associated antibody deficiency and immune dysregulation (PLAID or APLAID).

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مواضيع ذات صلة

Hemophagocytic lymphohistiocytosis

Allergic Rhinitis

Mechanisms of Immune Dysregulation in Autoimmune Disease

Chimeric Antigen Receptor T Cells

Checkpoint Inhibition Therapy for Cancer

Mechanisms of Regulation of T-Cell Activation

Neutrophils & Eosinophils Employ Nets to Entrap Parasites

Immunotherapy

Immune Tolerance and Autoimmunity

Cellular interactions in regulation of normal immune responses

Markers of Granulocytic Maturation

The Complement System Also Protects Against Infection