Along with generation of a diversified repertoire of T and B lymphocytes, purging of self-reactive cells is essential to maintain immune homeostasis and prevent autoimmune diseases. Some forms of primary immunodeficiency manifest with immune dysregulation due to genetic defects of central or peripheral T-cell tolerance.
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Syndrome
Also known as autoimmune polyglandular syndrome type 1 (APS1), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disorder characterized by auto immune endocrine manifestations (hypoparathyroidism, Addison disease), candidiasis, and nail dystrophy. The disease is caused by mutations of the autoimmune regulator (AIRE) gene, which encodes for a transcription factor expressed by medullary TECs (mTECs) where it regulates expression of tissue specific antigens that are presented to nascent T cells, thereby promoting clonal deletion of self-reactive T lymphocytes, or their conversion to natural regulatory T cells (nTreg cells).
In patients with APECED, mucocutaneous candidiasis usually develops first (in infancy or early childhood), followed by autoimmune hypoparathyroidism with hypocalcemia and adrenal failure. Around 15% to 20% of patients may develop insulin-dependent diabetes. Gastrointestinal and pulmonary involvement, reflecting auto immune damage, are frequently observed. Autoimmune hepatitis and ovarian failure are also common. Candidiasis may reflect elevated levels of antibodies to IL-17 and IL-22, which play an important role in the defense against Candida spp.
Management of patients with APECED is based on regular follow-up and searching for autoantibodies, which should be repeated every 6 months. Hormone-replacement therapy is indicated for the endocrinopathies. Aggressive management and prevention of candidiasis is important to avoid persistent or recurrent infections that may favor development of squamous cell carcinoma.
Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome
Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) is an X-linked disorder of systemic autoimmunity.120 Males with IPEX syndrome present early in life with skin rash, intractable watery diarrhea, insulin-dependent diabetes mellitus, lymphadenopathy, splenomegaly, and failure to thrive. Other autoimmune manifestations include thyroid disease, nephropathy, cytopenias, and vasculitis. In addition, patients with IPEX show elevated levels of IgE.
IPEX is caused by mutations of the FOXP3 gene, which encodes for a transcription factor that plays a critical role in the development and function of regulatory T (Treg) lymphocytes. These cells have suppressive functions; they have a distinctive phenotype (CD4+ CD25hi FOXP3+) and normally represent 5% to 15% of CD4+ circulating lymphocytes.
IPEX has a poor prognosis. Death often occurs within the first few years of life due to severe malabsorption, failure to thrive, metabolic derangement, or because of severe infections secondary to immune suppression. Use of immunosuppressive drugs (steroids, sirolimus, tacrolimus, rituximab) is necessary to treat the disease. However, the only definitive treatment is allogeneic SCT.
CD25 and STAT5B Deficiencies
IL-2 plays an important role in T lymphocyte proliferation and in immune homeostasis. Upon binding to the high-affinity IL-2 receptor, IL-2 promotes phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription (STAT)5, which drives expression of IL-2 target genes, including FOXP3. Autosomal recessive mutations of the IL2RA (CD25) gene, which encodes for the α chain of the IL-2 receptor, cause a disease that is associated with IPEX-like manifestations (lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, inflammatory bowel disease) and increased susceptibility to severe viral infections. A similar phenotype may also be caused by mutations of the IL2RB gene, encoding for the IL-2Rβ chain. HCT represents the only definitive treatment.
Autosomal recessive mutations of the STAT5B gene cause a syndrome characterized by autoimmunity (especially cytopenias and autoimmune hepatitis), eczema, severe and/or recurrent infections, lymphocytic interstitial pneumonia, and growth hormone (GH) insensitive dwarfism. The latter reflects the critical role played by STAT5 in the cellular response to GH. Affected patients have a low number of circulating T and NK lymphocytes and Treg cells, and in vitro proliferative responses to mitogens are reduced. In contrast, IgG levels are often elevated. Aggressive treatment of infections, use of immunosuppressive drugs to treat autoimmune manifestations, and regular monitoring of pulmonary function are the mainstay of treatment.
Cytotoxic T Lymphocyte Antigen 4 Deficiency
Cytotoxic T lymphocyte antigen 4 (CTLA4) is a surface molecule expressed by conventional and regulatory T cells. It competes with CD28 for binding to CD80/CD86 molecules expressed by antigen presenting cells. However, in contrast to CD28, CTLA4 delivers a suppressive signal that limits T-cell activation. Heterozygous loss-of function mutations of CTLA4 cause a condition characterized by lymphoid infiltrates in the lung, gastrointestinal tract, and the brain (simulating lymphoma), autoimmune cytopenias, hypogammaglobulinemia, lymphopenia, accumulation of activated T cells, and decreased Treg-cell function. The disease is inherited as an autosomal dominant trait with incomplete penetrance. Treatment is based on use of CTLA4-Ig (abatacept) and sirolimus. SCT may be considered in severe cases.
Lipopolysaccharide Responsive Beige-Like Anchor Protein Deficiency
Deficiency of the lipopolysaccharide responsive beige-like anchor protein (LRBA) is inherited as an autosomal recessive trait and causes a combined immunodeficiency with prominent immune dysregulation affecting mostly the gastrointestinal tract (with severe chronic diarrhea and failure to thrive) and the lungs. Autoimmune cytopenias are also common. Typical immunological abnormalities include hypogammaglobulinemia and a variable degree of lymphopenia, with increased proportion of activated T cells. The disease shares some clinical and immunologic manifestation similarities with CTLA4 deficiency. Indeed, LRBA binds to CTLA4 and allows endosomal trafficking of the latter to the cell membrane. In the absence of LRBA, CTLA4 is targeted to the lysosomal compartment where it is degraded. Consistent with this, Treg cells from patients with LRBA deficiency have low levels of expression of CTLA4 and FOXP3, and the actual number and function of Treg lymphocytes are impaired. Treatment with CTLA4-Ig (alone or in combination with sirolimus) may be beneficial.
DEF6 deficiency
Differentially expressed in FDCP 6 homolog (DEF6) is a guanine nucleotide exchange factor involved in TCR signaling. DEF6 deficiency affects availability of CTLA-4 at the cell surface and Treg function. Clinical manifestations include recurrent infections, enteropathy, cardiomyopathy and lymphoproliferation with hepatosplenomegaly.
Defects of Calcium Flux
T lymphocyte activation and homeostasis depend on calcium mobilization. In particular, TCR-induced activation results in release of Ca2+ from the endoplasmic reticulum stores, followed by Ca2+ entry through the Ca2+ release-activated channels (CRAC) located in the cell membrane. Mutations of STIM1 (which encodes for a sensor of endoplasmic reticulum calcium stores) and of ORAI1 (which encodes for CRAC) cause severe immunodeficiency in which T-lymphocyte generation in the thymus is not affected, but peripheral T cells are functionally impaired. Autoimmunity and nonprogressive myopathy are distinguishing features of these disorders.
Autoimmune Lymphoproliferative Syndrome
Interaction between FAS (CD95) on activated T and B lymphocytes, and Fas ligand (FASLG) on activated T cells triggers the extrinsic pathway to activation of the caspase cascade, culminating in apoptosis. In addition, cellular stress (including cytokine deprivation) may activate the intrinsic pathway of apoptosis, leading to disruption of mitochondrial membrane permeability, release of cytochrome c, activation of caspase 9 and apoptosis. Defects of FAS- or mitochondrial-dependent apoptosis are responsible for autoimmune lympho proliferative syndrome (ALPS), characterized by early-onset, chronic (>6 months), nonmalignant lymphoproliferation, autoimmunity, and increased risk of lymphoma.
The majority of patients with ALPS carry heterozygous dominant-negative mutations in the FAS (CD95, TNFRSF6) gene (ALPS FAS). Somatic mutations of the FAS gene are the second most common cause of the disease (ALPS-sFAS). More rarely, ALPS is caused by mutations of the FASLG gene (ALPS-FASLG), of caspase 8, caspase 10, Fas-associated death domain (FADD) protein, or by somatic activating mutations of N-RAS or K-RAS. Finally, autosomal recessive deficiency of protein kinase C (PRKCD), which plays an important role in regulating cell survival and apoptosis, also causes an ALPS-like disease with B-cell lymphoproliferative disease.
Lymphoproliferation, manifesting as lymphadenopathy, splenomegaly, or hepatomegaly, is the most common clinical manifestation, with a trend toward progressive remission in adulthood. More than 70% of ALPS patients develop autoimmune disease—most commonly immune cytopenias, less frequently organ-specific auto immunity. There is an increased risk of malignancies, especially EBV-associated non-Hodgkin lymphoma. Patients with PRKCD deficiency often present with SLE-like manifestations, with nephropathy and antiphospholipid antibody syndrome.
An immunologic signature of ALPS is the increased number of DN circulating T lymphocytes that express the αβ form of the TCR, but do not express CD4 or CD8 molecules. There is defective in vitro apoptosis of lymphocytes through the FAS-mediated or intrinsic pathway (depending on the genetic variant). Elevated levels of soluble FAS ligand, vitamin B12, and IL-10, hypergammaglobulinemia, and anti-phospholipid antibodies are often present in patients with ALPS FAS. By contrast, patients with PRKCD deficiency have low levels of IgG and an increased proportion of CD5+ B cells. Patients with caspase 8 deficiency, FADD deficiency, and PRKCD deficiency have recurrent infections. The number of DN T cells may be normal in patients with NRAS or KRAS mutations.
Treatment is based on immunosuppression (with steroids, rituximab, mycophenolate mofetil, or sirolimus) and surveillance for lymphoma. Splenectomy may improve cytopenias; however, relapse of autoimmunity has been observed in 50% of the splenectomized patients. Furthermore, severe, invasive bacterial infections have been reported in 30% of splenectomized patients, and the mortality rate for invasive bacterial infection after splenectomy is as high as 13.3%.
Other Conditions With Immune Dysregulation
STAT1 GOF mutations cause a variable clinical phenotype ranging from chronic mucocutaneous candidiasis to increased occurrence of viral, fungal, and bacterial infections, to autoimmunity.
GOF mutations of STAT3 cause increased STAT3 signaling and enhanced Th17 differentiation, with lymphoproliferation and solid-organ autoimmunity. The number of Treg cells is reduced.
GOF mutations of JAK1 cause an autosomal dominant condition with hypereosinophilia, hepatosplenomegaly, eosinophilic enteritis, poor growth and viral infections.
Deficiency of ITCH, an E3 ubiquitin ligase that regulates activation of phospholipase Cγ1 (PLCγ1), causes multiple autoimmune manifestations (enteropathy, thyroiditis, type 1 diabetes, hepatitis), interstitial lung disease, dysmorphic features, and develop mental delay.
Defects of IL-10 and IL-10R are responsible for very early onset inflammatory bowel disease.
Mutations of the tripeptidyl-peptidase II (TPP2) gene cause severe autoimmune hemolytic anemia, variable lymphoproliferation, and recurrent infections. Accelerated senescence of lymphoid cells and hypergammaglobulinemia are observed.
