Table IV.
Diseases of immune Dysregulaton
| Disease | Circulating T Cells | Circulating B cells | Serum Ig | Associated Features | Inheritance | Genetic defects, Presumed Pathogenesis |
|---|---|---|---|---|---|---|
| 1. Immuno-deficiency with hypopigmentation | ||||||
| (a) Chediak-Higashi syndrome | Normal | Normal | Normal | Partial albinism, giant lysosomes, low NK and CTL activities, heightened acute-phase reaction, encephalopathic accelerated phase | AR | Defects in LYST, impaired lysosomal trafficking |
| (b) Griscelli Syndrome, type 2 | Normal | Normal | Normal | Partial albinism, low NK and CTL activities, heightened acute phase reaction, encephalopathy in some patients | AR | Defects in RAB27A encoding a GTPase in secretory vescicles |
| (c) Hermansky-Pudlak syndrome, type 2 | Normal | Normal | Normal | Partial albinism, neutropenia, low NK and CTL activity, increased bleeding | AR | Mutations of AP3B1 gene, encoding for the β subunit of the AP-3 complex |
| 2. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes | ||||||
| (a) Perforin deficiency | Normal | Normal | Normal | Severe inflammation, fever, decreased NK and CTL activities | AR | Defects in PRF1; perforin, a major cytolytic protein |
| (b) Munc 13-D deficiency | Normal | Normal | Normal | Severe inflammation, fever, decreased NK and CTL activities | AR | Defects in MUNC13D required to prime vescicles for fusion |
| (c) Syntaxin 11 deficiency | Normal | Normal | Normal | Severe inflammation, fever, decreased NK and CTL activities | AR | Defects in STX11, involved in vescicle trafficking and fusion |
| 3. X-linked lymphoproliferative syndrome (XLP) | ||||||
| (a) XLP1 | Normal | Normal or reduced | Normal or low immunoglobulins | Clinical and immunologic abnormalities triggered by EBV infection, including hepatitis, aplastic anaemia, lymphoma | XL | Defects in SH2D1A encoding an adaptor protein regulating intracellular signals |
| (b) XLP2 | Normal | Normal or reduced | Normal or low immunoglobulins | Clinical and immunologic abnormalities triggered by EBV infection, including splenomegaly, hepatitis, hemophagocytic syndrome, lymphoma | XL | Defects in XIAP encoding an inhibitor of apoptosis |
| 4. Syndromes with autoimmunity | ||||||
| (a) Autoimmune lymphoproliferative syndrome (ALPS) | ||||||
| (i) CD95 (Fas) defects, ALPS type 1a | Increased double-negative (CD4− CD8−) T cells | Normal | Normal or increased | Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis increased lymphoma risk | AD (rare severe AR cases) | Defects in TNFRSF6, cell surface apoptosis receptor; in addition to germline mutations, somatic mutations cause similar phenotype, ALPS 1a (somatic) |
| (ii) CD95L (Fas ligand) defects, ALPS type 1b | Increased double-negative (CD4− CD8−) T cells | Normal | Normal | Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis, lupus | AD AR |
Defects in TNFSF6, ligand for CD95 apoptosis receptor |
| (iii) Caspase 10 defects, ALPS type 2a | Increased CD4− CD8− T cells | Normal | Normal | Adenopathy, splenomegaly, autoimmune disease, defective lymphocyte apoptosis | AD | Defects in CASP10, intracellular apoptosis pathway |
| (iv) Caspase 8 defects, ALPS type 2b | Slightly increased CD4− CD8− T cells | Normal | Normal or decreased | Adenopathy, splenomegaly, recurrent bacterial and viral infections, defective lymphocyte apoptosis and activation; | AD | Defects in CASP8, intracellular apoptosis and activation pathways |
| (v) Activating N-Ras defect, N-Ras ALPS | Increased CD4− CD8− T cells | Elevation of CD5 B cells | Normal | Adenopathy, splenomegaly, leukemia, lymphoma, defective lymphocyte apoptosis following IL-2 withdrawal | AD | Defect in NRAS encoding a GTP binding protein with diverse signaling functions, activating mutations impair mitochondrial apoptosis |
| (b) APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | Elevated CD4+ cells | Normal | Normal | Autoimmune disease, particularly of parathyroid, adrenal and other endocrine organs plus candidiasis, dental enamel hypoplasia and other abnormalities | AR | Defects in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance |
| (c) IPEX, immune dysregulation, polyendocrinopathy, enteropathy (X-linked) | Lack of CD4+ CD25+ FOXP3+ regulatory T cells | Normal | Elevated IgA, IgE | Autoimmune diarrhea, early onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema | XL | Defects in FOXP3, encoding a T cell transcription factor |