Immunodeficiency affecting cellular and humoral Immunity

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Immunodeficiency Main Page




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]


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.


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
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 deficiency
DOCK8 deficiency
CD3Y deficiency
DOCK2 deficiency
IL2IR deficiency
Present: MAGT 1 deficiency,LCK deficiency, UNC119 deficiency
ZAP70 deficiency
MST1 deficiency
RHOH deficiency
CARDII deficiency(LOF)
MALT1 deficiency
MHC1 deficiency
IL21 deficiency
TCR alpha deficiency
BCL10 deficiency
NIK deficiency
BCL11B deficiency
IKBKB deficiency
Moesin deficiency
OX40 deficiency
ICOS deficiency
LAT deficiency
TFRC deficiency
RelB deficiency
CD40 ligand deficiency(CD154)

γc (IL-2Rγ) deficiency

JAK-3 deficiency





CD45 deficiency

Coronin-1A deficiency

Winged helix deficiency/Nude SCID

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

Magnesium Transporter Gene (MAGT1) Deficiency, Lymphocyte-Specific Protein Tyrosine Kinase (LCK) Deficiency, UNC119 Deficiency

CD8 Deficiency

  • CD8 glycoproteins play vital role in both the maturation and function of MHC class I-restricted T lymphocytes.[36]
  • CD8 deficiency is autosomal recessive familial condition.
  • There is 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.

Zeta-Chain-Associated Protein Kinase 70 (ZAP70) Deficiency

Major Histocompatibility Complex 1 Deficiency

Dedicator of Cytokinesis 8 (DOCK8) Deficiency

Macrophage Stimulating 1 Deficiency

Interleukin 21 Deficiency

NF-κB inducing kinase Deficiency

  • It is caused by mutation in MAP3K14.

Moesin Deficiency

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.[49]
  • 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.[50]
  • Ras homolog gene family H (RHOH) deficiency leads to T cell defects and persistent HPV infections.[51]
  • 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.[52]
  • T-cell receptor-alpha deficiency is autosomal recessive disorder.[53]
  • 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.[54]
  • BCL11B gene encodes a zinc-finger transcription factor involved in hematopoietic progenitor cell development.[55]
  • Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development.[56]

OX40 Deficiency

  • It is an autosomal recessive disorder. [57]
  • 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.[58]
  • 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.[59]
  • 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.[60]
  • Caspase recruitment domain 11 (CARD11) is fundamental signaling component that mediates TCR-induced NF-kappa B activation.[61]
  • 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.[62]
  • 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).[63]
  • 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.[64]
  • 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.[65]
  • 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.[66]
  • 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.[67]
  • CD40 ligand (CD154), present on activated CD4-positive T cells.[68]
  • Ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion.[69]
  • 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.[70]
  • 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.[45]

MALT1 Deficiency


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