Immunodeficiency affecting cellular and humoral Immunity

# Overview
Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies are genetically determined and can be hereditary; secondary immunodeficiencies are acquired and much more common.  combined immune defect affecting both types of acquired immunity, i.e. both cellular and humoral responses. Acquired immunity remembers when it encounters an invading foreign cell or molecule antigen and quickly mounts a specific response on subsequent encounters. Cellular acquired responses are mediated by T cells, also called T lymphocytes, which kill infected cells, help B cells, and control the immune response. Humoral immunity is mediated by B cells which produce antibodies immunoglobulins that help T cells and other immune cells to recognize and attack antigens.

# Classification

## Severe Combined Immunodeficiency (SCID)

## Combined Immunodeficiencies Generally Less Pronounced than Severe Combined Immunodeficiency

# c (IL-2R) deficiency
- X-linked transmission.
- It is caused by mutation in the gene encoding the gamma sub-unit of interleukin-2 receptor (IL2RG).
- Patients present with repeated bacterial, viral and fungal infections, lack of delayed hypersensitivity and failure to thrive.
- HSCT is the mainstay of treatment.

# JAK-3 deficiency
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the Janus kinase-3 gene on chromosome 19.
- It has a similar presentation to X-linked SCID as above.
- HSCT is the mainstay of treatment.

# IL7a
- Autosomal recessive (AR) transmission
- It is caused by homozygous or compound heterozygous mutation in the interleukin-7 receptor gene on chromosome 5.
- It has a similar presentation to X-linked SCID as above

# CD3D
- Autosomal recessive (AR) transmission
- It is caused by mutation in the delta chain of the T3 T-cell antigen (OKT3) on chromosome 11.
- Patients present with recurrent infections and failure to thrive.
- HSCT is the mainstay of treatment. 

# CD3E
- Autosomal recessive (AR) transmission.
- It is caused by mutation in the epsilon gene of T3 T-cell antigen on chromosome 11.

# CD247
- Autosomal recessive (AR) transmission.
- It is caused by homozygous mutation in the CD247 (CD3Z) gene on chromosome 1.

# CD45 deficiency
- Autosomal recessive (AR) transmission.
- It is caused by mutation in the CD45 gene on chromosome 1.

# Coronin-1A deficiency
- Autosomal recessive (AR) transmission.
- It is caused by mutation in the CORO1A gene (which encodes an actin-regulating protein that is expressed mainly in hematopoietic cells) on chromosome 16.

# Winged helix deficiency/Nude SCID
- Autosomal recessive (AR) transmission.
- It is caused by a mutation in the FOXN1 gene (a transcription factor essential for the development and function of thymic epithelial cells) on chromosome 17. 
- Patients usually have the clinical triad of athymia, congenital alopecia universalis and nail dystrophy and present in early few months of life with severe, recurrent infections.CNS defects have also been reported which include anencephaly and spina bifida.
- Initial management includes immediate referral to a specialist center in suspected patients and providing supportive care until a definitive diagnosis reached.
- Prophylaxis and early treatment of infections is also an important step in management.

# ADA deficiency
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the adenosine deaminase gene (ADA) on chromosome 20.
- Patients have chondrosternal dysplasia, neurologic abnormalities like movement disorders, nystagmus, sensorineural deafness and cognitive defects, and also hepatic dysfucnction.
- Treatment options include:
Enzyme replacement therapy: Pegademase bovine (PEG-ADA) is used as the replacement therapy.
Bone marrow transplantation.
- Enzyme replacement therapy: Pegademase bovine (PEG-ADA) is used as the replacement therapy.
- Bone marrow transplantation.

# Reticular dysgenesis
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the mitochondrial adenylate kinase-2 gene (AK2) on chromosome 1.
- Patients present with agranulocytosis, lymphopenia and sensorineural hearing loss.
- Bone marrow transplant is the treatment of choice.

# DNA Ligase IV deficiency
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the LIG4 gene on chromosome 13.
- Patients show unusual facial features, microcephaly, developmental delay, pancytopenia, and various skin abnormalities.

# CERNUNNOS/XLF deficiency
- Autosomal recessive (AR) transmission.
- It is caused by mutations in the NHEJ1 gene on chromosome 2.
- It is characterized by microcephaly, growth retardation and sensitivity to ionizing radiation.

# DNA PKcs deficiency
- Autosomal recessive (AR) transmission.
- It is caused by a mutation in the PRKDC gene on chromosome 8.

# RAG 1/2 deficiency
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutations in the RAG1 and RAG2 genes on chromosome 11.
- Patients present with persistent diarrhea, candidiasis, lung infections, fever, and opportunistic infections.

# DCLRE1C deficiency
- Autosomal recessive (AR) transmission.
- It is caused by mutation in the gene encoding Artemis in chromosome 10.

# Combined Immunodeficiencies Generally Less Pronounced than Severe Combined Immunodeficiency

# Major Histocompatibility Complex II Deficiency
- Major Histocompatibility Complex class II deficiency, called as the bare lymphocyte syndrome type II.
- It is a rare autosomal recessive disorder.
- Lack of constitutive and inducible MHC class II expression in all cell types and tissues.

# Magnesium Transporter Gene (MAGT1) Deficiency, Lymphocyte-Specific Protein Tyrosine Kinase (LCK) Deficiency, UNC119 Deficiency
- Magnesium transporter gene (MAGT1) deficiency, T-cell tyrosine kinase Lck deficiency and Signaling adaptor protein Uncoordinated 119 (Unc119) deficiency related with a condition called Idiopathic CD4 lymphopenia. 
- MAGT1 deficiency stops the Mg (2+) influx, which impairs responses to antigen receptor engagement and successive steps like activation of phospholipase C1 and Ca(2+) influx in T cells but not B cells.
- Lck is vital for both CD4 and CD8 T-cell development and function. LCK deficiency decrease T cell proliferation.
- Unc119 is necessary for activation of T-cell tyrosine kinase Lck. Unc119-deficiency reduce the activity of LCK and decrease interleukin 2 production and cellular proliferation.

# CD8 Deficiency
- CD8 glycoproteins play vital role in both the maturation and function of MHC class I-restricted T lymphocytes.
- CD8 deficiency is autosomal recessive familial condition.
- There is single mutation in the CD8 gene that is due to missense mutation (gly90-->ser) in both alleles of the immunoglobulin domain of the CD8 alpha gene.

# Zeta-Chain-Associated Protein Kinase 70 (ZAP70) Deficiency
- ZAP70 gene encodes a tyrosine kinase that is important for T-cell signaling.
- ZAP70 deficiency, results in loss of the activity of this kinase.
- ZAP70 is expressed mostly in T and NK cells, deficiency causes dysregulated T cells.

# Major Histocompatibility Complex 1 Deficiency
- It is autosomal recessive disorder also called as Bare lymphocyte syndrome type I.
- It is extremely rare condition, less than 30 patients reported worldwide.
- There is homozygous inactivating mutation of transporter associated with antigen processing (TAP), which helps in peptide loading on MHC1.

# Dedicator of Cytokinesis 8 (DOCK8) Deficiency
- It is previously known as autosomal recessive hyper-IgE syndrome.
- Absence of DOCK8 expression impairs T cell expansion, which causes T cell lymphopenia and susceptibility to cutaneous viral infections.
- Clinical manifestation includes eczema, recurrent skin abscesses, pneumonias, and elevated serum IgE.

# Macrophage Stimulating 1 Deficiency
- Macrophage stimulating 1 encoded by gene contains four kringle domains and a serine protease domain.
- Macrophage Stimulating 1 (MST1) deficiency causes increased cell death of naive and proliferating T cells.
- MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2.

# Interleukin 21 Deficiency
- IL-21 is produced by activated T cells.
- IL-21 targets lymphoid and myeloid cells and regulates innate and acquired immune responses.
- Homozygous loss-of-function mutations in the interleukin-21 receptor gene is one cause of IL21 deficiency.
- IL-21 deficiency causes impaired proliferation and immunoglobulin class-switching in B cells.

# NF-B inducing kinase Deficiency
- NF-B-inducing kinase (NIK) is involved in lymphoid organogenesis through lymphotoxin- receptor signaling.
- NIK deficiency is autosomal recessive disorder.
- It is caused by mutation in MAP3K14.

# Moesin Deficiency
- It is newly described X linked combined immunodeficiency.
- It present early in life with lymphopenia and hypogammaglobulinemia.
- There is poor immune response to vaccine antigens, and increased susceptibility to bacterial and ] (VZV) infections.
- This immunodeficiency is caused by genetic defects of the moesin (MSN) gene.

# CD3Y Deficiency
- Deficiency of the CD3Y component of the TcR/CD3 complex is associated with a long-term severe defect of peripheral blood CD4+ CD45RA+ and CD8+ lymphocytes, whereas CD4+CD45RO+, B and natural killer lymphocytes are unaffected.
- These results suggest that the CD3Y site of the TcR/CD3 complex is required for the peripheral representation of certain T cell types.

# RHOH Deficiency
- Ras homolog gene family H (RhoH) is a membrane-bound adaptor protein that helps in proximal T-cell receptor signaling.
- Ras homolog gene family H (RHOH) deficiency leads to T cell defects and persistent HPV infections.
- RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells.

# T-cell Receptor Alpha Deficiency
- The alpha chain is synthesized by recombination joining of single V segment with a J segment.  Recombination of many different V segments with several J segments provides a wide range of antigen recognition.
- T-cell receptor-alpha deficiency is autosomal recessive disorder.
- It is caused by homozygous mutation in the TRAC gene on chromosome 14q11.

# BCL11B Deficiency
- BCL11B is required for T-cell differentiation and have vital role in the transcriptional regulation of these genes.
- BCL11B gene encodes a zinc-finger transcription factor involved in hematopoietic progenitor cell development.
- Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development.

# OX40 Deficiency
- It is an autosomal recessive disorder. 
- OX40 is a co-stimulatory receptor expressed on activated T cells.
- Its ligand, OX40L, is expressed on various cell types, including endothelial cells.
- OX40L was abundantly expressed in Kaposi Sarcoma lesions.
- OX40 deficiency causes low proportion of effector memory CD4(+) T cells in the peripheral blood.

# LAT Deficiency
- Linker for Activation of T cell (LAT) is substrate of the ZAP70 tyrosine kinase.
- LAT is phosphorylated on multiple tyrosines and serve as docking sites for many effector molecules.
- Germ line LAT deficiency causes early thymocyte developmental arrest and complete absence of peripheral T cells.
- LAT mutations results in premature LAT truncation, diminishing known tyrosine phosphorylation sites.

# DOCK2 Deficiency
- Dedicator of cytokinesis 2 gene (DOCK2) deficiency is autosomal recessive disorder.
- It causes defect in the chemokine-induced migration and actin polymerization.
- DOCK2 deficiency affects T cells, B cells function and NK-cell degranulation.

# CARD11 Deficiency
- It is autosomal recessive primary immunodeficiency with normal numbers of T and B lymphocytes, but defective intracellular signaling.
- Caspase recruitment domain 11 (CARD11) is fundamental signaling component that mediates TCR-induced NF-kappa B activation.
- Deficiency in CARD11 proceeds to impaired activation of NF-kappa B and also defect in interleukin-2 (IL-2) production.

# BCL10 Deficiency
- BCL10 is an autosomal recessive disorder.
- Complete BCL10 deficiency affects both hematopoietic and nonhematopoietic immunity.
- It presents with Homozygous loss-of-expression and loss-of-function mutation of BCL10.
- NF-B-mediated fibroblast functions were drastically affected.

# IKBKB Deficiency
- IKBKB encodes IB kinase 2 (IKK2, also known as IKK).
- Deficiency of IKBKB causes loss of expression of IKK2, also known as IKK-nuclear factor B (NF-B) pathway.
- IKBKB deficiency results in impairment of adaptive and innate immunity.

# ICOS Deficiency
- Inducible co-stimulator (ICOS) deficiency causes combined B- and T-cell immunodeficiency.
- Genetic diagnosis is the only tool to differentiate ICOS deficiency from other immunological defects.
- Antibody deficiency, autoimmunity, and combined immunodeficiency should be screened for ICOS mutations.
- ICOS deficiency was the first monogenic defect that cause common variable immunodeficiency (CVID)-like disease.

# TFRC Deficiency
- TFRC deficiency is autosomal recessive disorder.
- TFRC gene encodes the transferrin receptor, which is essential for cellular iron uptake.
- TFRC gene mutation causes defected TfR1 internalization motif and receptor endocytosis.

# ReIB Deficiency
- RelB is an NF-B family transcription factor.
- Homozygous mutation in the gene for the NFB transcription factor RelB causes repeated infection.
- This mutation introduces a premature stop codon, which results in an ablation of RelB expression.
- There is diminished antibody response to immunizations.

# CD40 ligand Deficiency
- CD40 ligand (CD40L) deficiency leads to opportunistic infections.
- CD40 ligand (CD154), present on activated CD4-positive T cells.
- Ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion.
- CD40L defects results in the failure of B cells to undergo immunoglobulin class switching.

# IL21R Deficiency
- IL21R is type I cytokine receptors, which also include receptors for hematopoietic growth factors.
- IL21R deficiency ceases proliferation and maturation of natural killer (NK) and B-cell.
- IL21R deficiency also stop immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity.

# MALT1 Deficiency
- MALT1 vital for immune receptor-driven signaling pathways which leads to NF-B activation.
- MALT1 deficiency leads to reduced T cell proliferation, defective IL-2 and TNF- production, as well as impaired Th17 differentiation.
- MALT1 deficiency also impaired nuclear factor-B activation and IL-2 production.