Immunodeficiency affecting cellular and humoral Immunity

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Overview

Classification

Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Zahir Ali Shaikh, MD[3], Anmol Pitliya, M.B.B.S. M.D.[4], Syed Musadiq Ali M.B.B.S.[5]

Overview

Classification


 
 
Immunodeficiency affecting cellular and humoral immunity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe combined immunodeficiencies SCID, defined
by CD3 T cell lymphopenia
 
Combined immunodeficiencies generally less pronounced
than severe combined immunodeficiency
 


Severe Combined Immunodeficiency (SCID)


 
 
 
 
 
 
 
 
 
Severe combined immunodeficiencies SCID, defined by CD3 T cell lymphopenia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD19 NL: SCID T-ve B+ve
 
 
 
 
 
 
 
CD19 ↓: SCID T-ve B-ve
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID T-ve B+ve NK-ve
 
 
 
SCID T-ve B+ve NK+ve
 
SCID T-ve B-ve NK-ve
 
 
 
SCID T-ve B-ve NK+ve
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
yc deficiency
 
 
 
 
IL7Ra .
 
 
ADA def
 
Microcephaly present
 
 
Microcephaly absent
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
JAK-3 def
 
 
 
 
CD3D, CD3E, CD247
 
 
Reticular dysgenesis
 
 
 
DNA Ligase IV def
 
 
 
RAG1/2 def
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD45 def
 
 
 
 
 
 
 
XLF def
 
 
 
DCLRE1C def
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coronin-1A def
 
 
 
 
 
 
 
DNA PKcs def
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Winged helix def
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Combined Immunodeficiencies Generally Less Pronounced than Severe Combined Immunodeficiency


 
 
 
 
 
 
 
 
 
 
 
 
 
Combined immunodeficiencies generally less pronounced than severe combined immunodeficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low CD4: MHC II Expression?
 
 
Low CD8
 
 
Low B Cells
 
 
 
Ig: Often Normal
 
 
Ig Low
 
 
Normal Ig but Low Specific Antibody Response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Absent: MHCII Deficiency
 
 
 
CD8 def:
 
 
 
DOCK8 def:
 
 
 
 
CD3Y def:
 
 
 
DOCK2 def:
 
 
 
IL2IR Def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Present: MAGT 1 Def:,LCK Def:, UNC119 Def:
 
 
 
ZAP70 def:
 
 
 
MST1 def:
 
 
 
 
RHOH def:
 
 
 
CARDII def:(LOF)
 
 
 
MALT1 Def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MHC1 def:
 
 
 
IL21 def:
 
 
 
 
TCR alpha def:
 
 
 
BCL10 def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NIK def:
 
 
 
 
BCL11B def:
 
 
 
IKBKB Def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moesin def:
 
 
 
 
OX40 def:
 
 
 
ICOS def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LAT def
 
 
 
TFRC def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RelB def:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD40 ligand def:(CD154)
 
 
 
 
 
 
 


γc (IL-2Rγ) 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.[1]
  • HSCT is the mainstay of treatment.[2]

JAK-3 deficiency

IL7a

CD3D

CD3E

CD247

CD45 deficiency

Coronin-1A deficiency

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. [13][14]
  • 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.[15]CNS defects have also been reported which include anencephaly and spina bifida.[16]
  • Initial management includes immediate referral to a specialist center in suspected patients and providing supportive care until a definitive diagnosis reached.[17]
  • Prophylaxis and early treatment of infections is also an important step in management.[18]

ADA deficiency

Reticular dysgenesis

DNA Ligase IV deficiency

CERNUNNOS/XLF deficiency

DNA PKcs deficiency

RAG 1/2 deficiency

DCLRE1C deficiency

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.[31]

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. [32]
  • MAGT1 deficiency stops the Mg (2+) influx, which impairs responses to antigen receptor engagement and successive steps like activation of phospholipase Cγ1 and Ca(2+) influx in T cells but not B cells.[33]
  • Lck is vital for both CD4 and CD8 T-cell development and function. LCK deficiency decrease T cell proliferation.[34]
  • 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.[35]

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.
  • Single mutation in the CD8α gene that is due to missense mutation (gly90-->ser) in both alleles of the immunoglobulin domain of the CD8 alpha gene[36]

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[37]
  • ZAP70 is expressed mostly in T and NK cells, deficiency causes dysregulated T cells[38]

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[39]
  • There is homozygous inactivating mutation of transporter associated with antigen processing (TAP), which helps in peptide loading on MHC1[40]

Dedicator of Cytokinesis 8 (DOCK8) Deficiency

  • It is previously known as autosomal recessive hyper-IgE syndrome[41]
  • 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 (MST1) deficiency causes increased cell death of naive and proliferating T cells.[42]
  • MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2.

Interleukin 21 Deficiency

  • Homozygous loss-of-function mutations in the interleukin-21 receptor gene is one cause of IL21 deficiency.[43]
  • IL-21 deficiency causes impaired proliferation and immunoglobulin class-switching in B cells.

NF-κB inducing kinase Deficiency

  • NIK deficiency is autosomal recessive disorder[44]
  • It is caused by mutation in MAP3K14.

Moesin Deficiency

  • It is newly described X linked combined immunodeficiency[45]
  • It present early in life with lymphopenia and hypogammaglobulinemia.
  • There is poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus (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[46]
  • 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) deficiency leads to T cell defects and persistent HPV infections[47]
  • RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells.

T-cell Receptor Alpha Deficiency

  • T-cell receptor-alpha deficiency is autosomal recessive disorder[48]
  • It is caused by homozygous mutation in the TRAC gene on chromosome 14q11.

BCL11B Deficiency

  • BCL11B gene encodes a zinc-finger transcription factor involved in hematopoietic progenitor cell development[49]
  • Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development[50]

OX40 Deficiency

  • It is an autosomal recessive disorder. [51]
  • 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[52]
  • 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[53]
  • 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

  • Caspase recruitment domain 11 (CARD11) is fundamental signaling component that mediates TCR-induced NF-kappa B activation[54]
  • 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[55]
  • Complete BCL10 deficiency affects both hematopoietic and nonhematopoietic immunity.
  • It presents with Homozygous loss-of-expression and loss-of-function mutation of BCL10.
  • NF-κB-mediated fibroblast functions were drastically affected.

IKBKB Deficiency

  • IKBKB encodes IκB kinase 2 (IKK2, also known as IKKβ)[56]
  • Deficiency of IKBKB causes loss of expression of IKK2, also known as IKK-nuclear factor κB (NF-κB) 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[57]
  • 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[58]
  • 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-κB family transcription factor[59]
  • Homozygous mutation in the gene for the NFκB 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[60]
  • CD40 ligand (CD154), present on activated CD4-positive T cells[61]
  • Ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion[62]
  • 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[63]
  • 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[43]

MALT1 Deficiency

  • MALT1 vital for immune receptor-driven signaling pathways which leads to NF-κB activation[64]
  • MALT1 deficiency leads to reduced T cell proliferation, defective IL-2 and TNF-α production, as well as impaired Th17 differentiation.
  • MALT1 deficiency also impaired nuclear factor-κB activation and IL-2 production[65]

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