Diseases of immune dysregulation

# Overview
Immune dysregulation involves a variety of subcategories including hemophagocytic lymphohistiocytosis, EBV-related dysregulation, and autoimmunity.

# Classification

## Hemophagocytic Lymphohistiocytosis (HLH) & EBV Susceptibility

## Syndromes with Autoimmunity and Others

# Chediak Higashi Syndrome
- Chediak Higashi syndrome is caused by homozygous or compound heterogenous autosomal recessive mutation in the lysosomal trafficking gene (LYST) on chromosome1q42.
- It is characterized by photophobia, nystagmus, partial albinism, neutropenia, abnormal susceptibility to infections and malignant lymphoma, large eosinophilic peroxidase positive inclusion bodies in myeloblasts and promyelocytes of bone marrow.
- The most effective treatment is hematopoeitic stem cell transplantation.
- For more information on Chediak Higashi syndrome, click here.

# Griscelli Syndrome type 2
- Griscelli syndrome type 2 is a rare autosomal recessive disease caused by mutation in the RAB27A gene. 
- It is characterized by partial albinism, immunodeficiency, organomegaly and accelerated phases which includes hemophagocytosis, pancytopenia and neurological deterioration.
- The only curative treatment is hematopoeitic stem cell transplantation.

# Hermansky Pudlak Syndrome type 2
- Hermansky pudlak syndrome type 2 is caused by homozygous or compound heterogenous autosomal recessive mutation in the gene encoding the beta-3A subunit of AP3 complex (AP3B1) on chromosome 5q14.
- It is characterized by platelet defects, oculocutaneous albinism, immunodeficiency, congenital neutropenia and pulmonary fibrosis.
- Treatment includes chronic antibiotic therapy and granulocyte colony stimulating factor (G-CSF) because of neutropenia and management of complications as they arise.

# Hermansky Pudlak Syndrome type 10
- Hermansky pudlak syndrome type 10 is caused by an autosomal recessive mutation in AP3D1 gene on chromosome 19p13.
- It is characterized by immunodeficiency, oculocutaneous albinism and severe neurological impairment including severely delayed global development and intractable seizures.
- Treatment depends upon the manifestations of disease, granulocyte-colony stimulating factor (G-CSF) used when immunodeficiency is present.

# Perforin Deficiency
- Perforin is a glycoprotein responsible for pore formation in cell membranes of target cells. The main source of perforin are natural killer (NK) cells and CD8 positive T cells. A low amount of perforin is also expressed by CD4 positive T cells.
- Diseases associated with perforin deficiency/defect include: hemophagocytic lymphohistiocytosis (HLH), leukemias, lymphomas, infectious diseases and autoimmune diseases.
- Treatment depends upon the presentation of disease.

# UNC13D/Munc13-4 Deficiency
- Munc13-4 is a RAB27A effector that coordinates exocytosis in hematopoietic cells, its deficiency is associated with human immunodeficiency familial hemophagocytic lymphohistiocytosis type 3.
- It is characterized by the features of hemophagocytic lymphohistiocytosis (HLH) including; fever, hepatosplenomegaly and cytopenias.
- The only curative treatment is allogenic hematopoietic stem cell transplantation.

# Syntaxin 11 Deficiency
- Syntaxin 11 deficiency is caused by homozygous mutation in the syntaxin 11 gene located on chromosome 6q24.
- Syntaxin 11 deficiency patients develop familial hemophagocytic lymphohistiocytosis 4(FHL4), characterized by fever, splenomegaly, bicytopenia, low/absent natural killer (NK) cell activity and increased ferritin.
- The only treatment available is hematopoietic stem cell transplantation.

# STXBP2/Munc18-2 Deficiency
- STXBP2/Munc18-2 deficiency is caused by homozygous or compound heterogenous mutation in the syntaxin binding protein-2 gene (STXBP-2) on chromosome 19p13. 
- STXBP2 deficiency causes familial hemophagocytic lymphohistiocytosis 5(FHL5), characterized by fever, hepatosplenomegaly, bicytopenia, increased triglycerides and ferritin with some atypical features including sensorineural hearing deficit, abnormal bleeding, or severe diarrhea.
- Treatment involves; immunosuppressive and modulatory agents, management of complications and hematopoietic stem cell transplantation.

# RASGRP1 Deficiency
- RASGRP1 is an important guanine nucleotide exchange factor and activator of RAS-MAPK pathway following T cell antigen receptor (TCR) signaling.
- RASGRP1 deficiency is caused by a mutation in RASGRP1 gene located on chromosome 15q14.
- RASGRP1 deficiency causes severe autoimmune manifestations, life threatening immune dysregulation and susceptibility to EBV induced B cell malignancies.
- Early diagnosis is important in management and hematopoietic stem cell transplantation is considered curative.

# CD70 Deficiency
- CD70 gene is located on chromosome 19p13.3. The protein encoded by this gene is a cytokine that belongs to TNF ligand family. This cytokine is a ligand for TNFRSF27/CD27.
- CD70 is a surface antigen located on activated, but not resting, T and B lymphocytes. It induces proliferation of costimulated T cells, enhances generation of cytotoxic T cells and contributes to T cell activation.
- Its deficiency causes combined immunodeficiencies and EBV associated lymphoproliferation.
- The treatment includes; immunosuppressive drugs like rituximab and hematopoietic stem cell transplantation.

# CTPS1 Deficiency
- CTPS1 gene is located on chromosome 1p34.2. It encodes an enzyme responsible for catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphosphate); which is an important step in the biosynthesis of phospholipids and nucleic acids.
- CTPS1 deficiency is caused by loss of function mutation in the gene, that causes life threatening immunodeficiency characterized by impaired capacity of activated B and T cells to proliferate in response to antigen receptor mediated activation.
- Treatment includes; management of compplications and hematopoietic stem cell transplantation.

# RLTPR (CARMIL2) Deficiency
- CARMIL2 gene is located on chromosome 16q22.1, which encodes a member of CARMIL (capping protein, Arp 2/3, myosin-I linker) family of proteins.The encoded protein interacts with & negatively regulates the heterodimeric capping protein and promotes cell migration. 
- CARMIL2 deficiency is associated with autosomal recessive human immunodeficiency disorder, resulting in defective CD28 cosignalling and inadequate T cell activation, proliferation, differentiation, effector function and T cell polarity and migration.
- It can present as failure to thrive, chronic diarrhea, recurrent skin and upper airway infections and psoriasis.

# ITK Deficiency
- ITK (Interleukin 2 inducible T cell Kinase) gene is located chromosome 5q33.3, encodes an intracellular tyrosine kinase expressed in T cells. It helps in T cell proliferation and differentiation.
- It can present as fever, lymphadenopathy, hepatosplenomegaly, pulmonary involvement, T cell depletion and hypogammaglobulinemia.
- Treatment options include; rituximab, IgG susbstitution and hematopoietic stem cell transplantation.

# MAGT1 Deficiency
- MAGT1 (magnessium transporter1) gene is located on chromosome Xq21.1, which encodes for a ubiquitously expressed magnessium cation transporter protein that localizes to cell membrane.
- MAGT1 deficiency is caused by loss of function mutation in MAGT1 which leads to an immunodeficiency called XMEN syndrome characterized by chronic EBV infection, CD4 lymphopenia and EBV related lymphoproliferative disorders.
- It can present as splenomegaly, dysgammaglobulinemia, persistent elevation in EBV viral load, EBV associated lymphoproliferative disorders and decreased CD4/CD8 ratio.
- Treatment options include; antibiotic prophylaxis, antiviral prophylaxis, immunoglobulin replacement therapy, chemotherapy including rituximab, oral Mg2+ supplementation and hematopoietic stem cell transplantation.

# PRKCD Deficiency
- PRKCD (protein kinase C delta) gene located on chromosome 3p21.1 is a member of protein kinase C family of serine and threonine specific protein kinases, activated by diacylglycerol and is both a tumor suppressor and positive regulator of cell cycle progression. This protein can also positively or negatively regulate apoptosis.
- PRKCD deficiency is associated with primary immunodeficiency with B cell deficiency and severe autoimmunity.
- It can manifest as hepatosplenomegaly, lymphadenopathy, antiphospholipid antibody syndrome, SLE like syndrome, CNS vasculitis and recurrent infections.
- Treatment includes; management of complications and hematopoietic stem cell transplantation.

# XLP1
- XLP1 (X linked lymphoproliferative disease type 1) also called as Duncan disease is caused by a mutation in the gene called SH2D1A located on chromosome Xq25.
- SH2D1A gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells.
- It can manifest as severe immune dysregulation, severe/fatal EBV infection, acquired hypogammaglobulinemia, hemophagocytic lymphohistiocytois (HLH), aplastic anemia, red cell aplasia and lymphomatoid granulomatosis. 
- The only definitive treatment available for XLP1 is allogenic hematopoetic stem cell transplantation.

# XLP2
- XLP2 (X linked lymphoproliferative syndrome type2) is caused by a mutation in the gene called XIAP (X linked inhibitor of apoptosis) located on chromosome Xq25.
- XIAP gene encodes a protein that belongs to a family of apoptotic suppressor proteins, members of this family share a baculovirus IAP repeat which is necessary for their anti-apoptotic function.
- XLP2 can present as; fever, splenomegaly, chronic EBV infection, colitis/IBD,hemophagocytic lymphohistiocytosis (HLH) and recurrent infections.
- Treatment includes; immunosuppressive agents such as steroids or etoposide or antithymocyte globulin, rituximab and IV immunoglobulin replacement therapy. The only curative treatment is allogenic hematopoietic stem cell transplantation (HST).

# CD27 Deficiency
- CD27 deficiency/Lymphoproliferative syndrome type 2 is an autosomal recessive disease caused by a mutation in CD27 gene located on chromosome 12p13.31.
- CD27 gene encodes a 
- It presents with persistent EBV viremia, hypogammaglobulinemia, hemophagocytic lymphohistiocytosis (HLH) and malignant lymphoma.
- Treatment includes; management of complications, rituximab and allogenic hematopoietic stem cell transplantation.

# FAAP24 Deficiency
- FAAP24 (fanconi anemia associated protein 24) plays a crucial role in DNA damage response, is located on chromosome 19q13.11.
- FAAP24 deficiency can present as EBV associated lymphoproliferative disease, fanconi anemia.

# Autoimmune Lymphoproliferative Syndrome(ALPS)
- Autoimmune lymphoproliferative syndrome is caused by immune dysregulation due to a defect in lymphocyte apoptosis.
- It occurs due to a mutation in the gene FAS (chromosome 10q23.31), but can also occur due to mutations in the genes FAS ligand (chromosome 1q24.3), caspase 10 (chromosome 9) and caspase 8 (chromosome 2q33.1).
- It can be transmitted in an autosomal recessive and dominant fashion.
- It presents as; lymphadenopathy, splenomegaly, increased risk of lymphoma and autoimmune disease which causes multilineage cytopenias.
- Treatment includes; corticosteroids, immunosuppressive drugs, IVIG, granulocyte colony stimulating factor (G-CSF), hematopoietic stem cell transplantation (HST).

# FADD Deficiency
- FADD (Fas associated via death domain) gene located on chromosome 11q13.3 encodes a protein adapter molecule that interacts with various cell surface receptors including TNF receptor superfamily and mediates cell apoptotic signals.
- FADD deficiency can present as recurrent infections, hepatic dsfunction, cardiovascular malformations, encephalopathy, decrease in hematopoietic stem cells and progenitor enriched population and autoimmune lymphoproliferative syndrome.
- Treatment includes; supportive management and hematopoietic stem cell transplantation.

# LRBA Deficiency
- LRBA (lipopolysaccharide responsive biege like anchor protein) gene located on chromosome 4q31.3 encodes a protein which associates with protein kinase A and may be involved in leading intracellular vesicles to activated receptor complexes, which aids in secretion and membrane deposition of immune effector molecules.
- LRBA deficiency can present as lymphoproliferation, autoimmunity, humoral immune deficiency, pure red cell aplasia, acquired amegakaryocytic thrombocytopenic purpura and IBD like symptoms.
- Treatment includes; immunosuppressive therapy, immunoglobulin replacement therapy and hematopoietic stem cell transplantation (HST).

# STAT3 GOF Mutations
- STAT3 (signal transducer & activator of transcription 3) gene located on chromosome 17q21.2 encodes a protein, which when phosphorylated and activated translocates to the nucleus and mediates the expression of variety of genes, playing a key role in many cellular processes such as cell growth and apoptosis.
- STAT3 GOF (STAT3 gain of function) mutation can present as; lymphocytic leukemia, myelodysplastic syndrome, aplastic anemia, infections, multiorgan autoimmune disease and short stature.
- Treatment includes; steroids, IVIG, rituximab, mycophenolic acid and hematopoietic stem cell transplantation.

# IL10 Deficiency
- IL10 (interleukin 10) gene located on chromosome 1q32.1 encodes a protein that has pleiotropic effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens & costimulatory molecules on macrophages. It also enhances B cell survival, proliferation & antibody production.
- IL10 deficency can present as; immune dysregulation and very early onset inflammatory bowel disease (VEO-IBD).
- The only curative treatment option is hematopoietic stem cell transplantation (HST).

## IL10RA Deficiency
- IL10RA (internleukin 10 receptor subunit alpha) gene located on chromosome 11q23.3 encodes a protein which is a receptor for interleukin 10. It mediates the [[immunosuppression
immunosuppressive]] signal for IL10 and thus inhibits the synthesis of proinflammatory cytokines.

## IL10RB Deficiency
- IL10RB (interleukin 10 receptor subunit beta) gene located on chromosome 21q22.11 encodes a protein which belongs to cytokine receptor family. It is an accessory chain essential for active interleukin 10 receptor complex. Cooexpression of this and IL10RA protein is required for IL10 induced signal transduction.

# NFAT5 Haploinsufficiency
- NFAT5 (nuclear factor of activated T cells 5) gene located on chromosome 16q22.1 encodes a protein, which is a member of activated T cells family of transcription factors. They play a central role in inducible gene transcription during immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells.
- NFAT5 haploinsufficiency presents with; autoimmune diseases, primary immunodeficiency syndromes, autoimmune enterocolopathy, decreased cytokines and NK cells and inflammatory bowel disease (IBD).
- Treatment includes supportive management and immunosuppressive drugs.

# Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)
- APECED or autoimmune polyendocrinopathy syndrome type 1 (APS1), an autoimmune recessive disease caused by a mutation in the gene called AIRE (autoimmune regulator) located on chromosome 21q22.3.
- The autoimmune regulator gene (AIRE) encodes a transciptional regulator which plays an important role in immunity by regulating the expression of autoantigens & negative selection of autoreactive  in thymus.
- APECED is characterized by presence of chronic candida infection, autoimmune hypoparathyroidism and addison's disease. At least two of these three major components need to be present for diagnosis.
- Other features of APECED include; ovarian failure, insulin dependant diabetes mellitus (IDDM), enamel hypoplasia, alopecia and nail dystrophy.
- Management of APECED involves treatment of its individual conditions and knowledge and high index of suspicion of this rare syndrome can lead to early detection and prevention of most of its complications.

# ITCH Deficiency
- ITCH (itchy E3 ubiquitin protein ligase)gene located on chromosome 20q11.22 encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases, which plays a role in multiple cellular processes including erythroid and lymphoid cell proliferation and regulation of immune responses.
- ITCH deficiency presents with hepatosplenomegaly, failure to thrive, developmental delay, dysmorphic features, relative macrocephaly, chronic lung disease and autoimmune diseases.
- Treatment includes; corticosteroids, azathioprine, rapamycin and tacrolimus.

# ZAP70 Mutations
- ZAP70 (zeta chain associated protein kinase 70) gene located on chromosome 2q11.2 encodes an enzyme belonging to protein tyrosine kinase family & plays a role in T cell development and lymphocyte activation. This enzyme is also essential for thymocyte development.
- ZAP70 mutations are associated with many autoimmune diseases including chronic lymphocytic leukemia (CLL) and severe combined immunodeficiency (SCID).
- Treatment of choice is hematopoietic stem cell transplantation (HST).

# Tripeptidyl Peptidase II deficiency (TPP2)
- TPP2 (tripeptidyl peptidase 2) gene located on chromosome 13q33.1 encodes a mammalian peptidase that at neutral PH, removes tripeptides from N terminus of longer peptides. The protein has a specialized function that is essential for some MHC class I antigen presentation.
- TPP2 deficiency causes recurrent infections, recurrent orolabial HSV-1 infections, early onset evan's syndrome,CNS SLE and developmental delays.
- Treatment of choice is heamatopoietic stem cell transplantation (HST).

# JAK1 GOF
- JAK1 (janus kinase1) gene located on chromosome 1p31.3 encodes a membrane protein that is a member of class of protein tyrosine kinases (PTK) that plays a role in interferon-alpha/beta and interferon gamma signal transduction.
- JAK1 GOF (gain of function) mutation causes autosomal dominant immune dysregulation, hypereosinophilia with eosinophilic infiltration of gastro interstinal tract, massive hepatosplenomegaly and atopic dermatitis.
- Treatment includes; ruxolitinib and hematopoietic stem cell transplantation (HST).

# Prolidase Deficiency
- Prolidase gene located on chromosome 19q13.11 encodes a member of peptidase family. It forms a homodimer that hydrolyzes dipeptides or tripeptides with C terminal proline or hydroxyproline residues. The enzyme has an important role in recycling of proline and may be rate limiting for production of collagen.
- Prolidase deficiency presents with skin lesions, recurrent infections, dysmorphic facial features, hepatomegaly with elevated liver enzymes, splenomegaly, intellectual disability, anemia, thrombocytopenia, and hypergammaglobulinemia.
- Treatment includes; treatment of manifestations and supportive treatment. There is no curative treatment available.

# IPEX (Immune dysregulation, Polyendocrinopathy,enteropathy)
- IPEX also called X-linked autoimmunity-immunodeficiency syndromes caused by a defect in the gene called FOXP3 (forkhead box P3) located on chromosome Xp11.23.
- FOXP3 gene encodes a protein member of forkhead/winged-helix family of transcriptional regulators.
- It is characterized by the clinical triad of watery diarrhea, endocrinopathy (commonly IDDM) and eczematous dermatitis. Other features include; splenomegaly, lymphadenopathy, cytopenias and autoimmune hepatitis or nephropathy.
- Treatment includes; management of the complications and hematopoietic stem cell transplantation (HST) remains the ony cure.

# CD25 Deficiency (IL2RA)
- CD25 deificiency is caused by IL10RA (internleukin 10 receptor subunit alpha) deficiency, whose gene located on chromosome 11q23.3 encodes a protein which is a receptor for interleukin 10. It mediates the immunosuppressive signal for IL10 and thus inhibits the synthesis of proinflammatory cytokines.
- CD25 deficiency can present with primary biliary cirrhosis, chronic and severe inflammatory lung disease and immune dysregulation, endocrinopathy, enteropathy, X linked like syndrome.
- Treatment includes; corticosteroids, rituximab, intravenous immunglobulin, cyclosporin, antibiotics and bone marrow transplantation.

# CTLA4 Deficiency (ALPSV)
- CLTA4 (cytotoxic T lymphocyte associated protein 4) gene located on chromosome 2q33.2 encodes a protein which transmits an inhibitory signal to T cells.
- CLTA4 deficiency can present with lymphadenopathy, splenomegaly, hypogammaglobulinemia, organ specific autoimmunity and lymphocytic infiltration of nonlymphoid organs.
- Treatment includes; abatacept, sirolimus, chloroquine and hematopoietic stem cell transplantation (HST).

# BACH2 Deficiency
- BACH2 (BTB domain and CNC homolog2) gene located on chromosome 6q15 encodes a transcription factor which represses its target genes and plays an important role in differentiation of T and B lymphoid cells.
- BACH2 deficiency can present with lymphadenopathy, splenomegaly, inflammatory bowel disease, chronic diarrhea and recurrent sinopulmonary infections.
- Treatment includes hematopoietic stem cell transplantation (HST).