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immunodeficient people
most relevant system to study the function of a gene
observe the phenotype
characteristics of primary immunodeficiencies
history of repeated infections: bacteria (humoral defect), virus/ fungi (cellular defect)
the best source of information regarding the immune system
immune redundancy: some people with an inactivated immune gene are healthy
may affect innate or adaptive immunity
Severe combined immunodeficiency SCID
affects both T & B lymphocytes (humoral & cellular immunity)
no T-cells are considered SCID because no T-cells help B-cells
mutations affecting only B-cell development or CD8+ T-cell development immunodeficiency but not severe
mutations affecting T/B development
many deficiencies at different stages of B-&T-cell development
XSCID
IL-2/-4/-7/-9/-15/-21 share a common γ chain that is coded on the X chromosome
impaired cytokine signaling
ßc / JAK3 mutation
inactivated common ß-chain
signaling of cytokines affected
needed for T-cell maturation & T-cell help for B-cells
JAK needed for maturation
->SCID
IL-7Rα
the mutation prevents maturation to pro-T-cell
RAG1, RAG2
no TCR rearrangement
no TCR+ T-cells
Artemis, DNA-PKc, DNA ligase IV
enzymes involved in DNA rearrangement
TCR & BCR rearrangement
AIRE
self-reactivity multiorgan & autoantibodies against key cytokines (e.g. IFNg, IL-17)
impaired negative selection in T-cell development = systemic auto-immunity
immunodeficient because not tolerant against important cytokines -> auto-immunity & immunodeficiency
CIITA, RFXANK, RFX5, RFXAP
MHC class II deficiency
TF necessary to produce MHCII -> not possible to select CD4+ T-cells
SCID as no B-cell collaboration is possible
CD3δ/γ/ζ
impaired CD3 signaling -> impairs pro-T-cell to pre-T-cell transition
CD45
pre-TCR to double-positive T-cell transition impaired
ZAP-70
SCID-like immunodeficiency (tyrosine kinase in signaling involved)
impairs maturation from double-positive T-cell to CD8+ T-cell
TAP1/TAP2/Tapasin
transport & loading of peptides affected
MHC class I deficiency
no positive selection-> no SCID as the humoral response is not affected
ADA
transition of common lymphoid progenitor to pro-B-cell or pro-T-cell impaired
adenosine deaminase involved in purine salvage pathway
converts adenosine to inosine & deoxyadenosine to deoxyinosine
deoxyadenosine tosic to CLP -> no B&T-cells formed
μH, λ5, Igα, Igß
B-cell deficiency (equivalent to CD3)
no SCID -> only humoral response affected
pro -> pre-B-cell
BLNK
B-cell deficiency
involved in the first signaling
total B-cell deficiency
pre-B-cell to immature B-cell transition
BTK
X-linked agammaglobulinemia
B-cell specific -> involved in B-cell maturation
reduces the possibility of producing IgG (γ-globulin)
problem in class switch
most common mutations in SCID
common γ-chain
TCR/BCR generation
Agammaglobulinemia
Bruton tyrosine kinase carried on X-chromosome & specific for B-cell signaling
contains a P (pleckstrin) H domain & binds phosphorylated lipids
XLA male: only 1X -> total B-cell deficiency if they carry the mutation
carrier female (heterozygous): mix of cells depending on random X inactivation in B-cells
have normal & defective B-cells -> no complete B-cell deficiency
normal B-cell development proceeds through a stage in which the pre-B-cell receptor transduces a single via BTA triggering further B-cell development -> no signal transduction in XLA
Wiskott-Aldrich syndrom
mutations in genes that don’t affect T-cell development
changes after T-cell activation in actin polymerization & TF produced
in homozygous inactivation of WASp SCID phenotype
no actin polymerization upon T-cell activation possible
Common variable immunodeficiencies CVID
less severe
B-cell deficiency (partial)
defect in immunoglobulin production but usually not all isotypes are affected
heterogenous group of disorders
CD40L/NEMO
X-linked hyper-IgM syndrome
NEMO: last immune signaling in the activation of TF NFκB
CD40/CD40L interaction defect impairs class switch
not only T-cell help but also Th1 activating macrophages deficient
CD40
hyper-IgM syndromes
AID, UNG, TAC, CD19, ICOS
B-cell intrinsic hyper-IgM syndromes or CVIDs -> doesn’t affect the activation of macrophages
differentiation B-cell in Ab secreting plasma cells
class switch & somatic hypermutation
ICOS: CD28 subfamily, expressed in GC B-cells, signaling by follicular DC important for differentiation into a plasma cell
CD19: expressed on all B-cells, important in differentiation into Ab-producing plasma cells
IgA deficiency
unknown mutated genes
1 specific isotype can’t be produced
Hyper-IgM syndrome
some key genes without redundancy
1 mutation with drastic phenotype
in hyper IgM syndrome: lymph node without germinal centers (e.g. inactivated CD40)
in normal lymph node with GC: circles visible -> ring of dense cells = germinal center in SLO
inside GC-activated B-cell proliferation pushing away non-Ag specific B-cells
Complement deficiencies
almost everything can be inactivated
inactivation in many different genes -> system not redundant
associated with susceptibility to certain infections & accumulation of immune complexes
Innate immune deficiencies
different cell types affected
congenital neutropenias: inherited decrease in neutrophils ->e.g. elastase 2 deficiency -> more bacterial infections
leukocyte adhesion deficiency (LFA-1 & other integrins): widespread pyogenic bacterial infections
TLR signaling defects (MyD88 or IRAK4): severe cold pyogenic bacterial infections
chronic granulomatous disease (ROS deficiency): intracellular & extracellular infection, granulomas (fused infected macrophages)
myeloperoxidase deficiency: defective intracellular killing, chronic infection
treatment - allogeneic hematopoietic stem cell transplantation
new T-&B-cells with the correct gene
but graft vs. host disease
treatment - gene therapy
SCID (ZAP-70) retrovirus: modified HIV integrates in CD4 T-cells but no replication
gain CD4 function & humoral response but CD8 still dysfunctional
cured but 5/10 develop T-cell leukemias -> uncontrolled retrovirus insertion
ZAP-70 too efficient -> too much signaling
treatment-induced pluripotent stem cells
generation of stem cells from somatic cells (fibroblasts) for in vitro gene therapy)
reprogram with specific cytokine cocktail to stem cell
certain cytokine for hematopoietic stem cell maturing in healthy B-& T-cell in patient
acquired immunodeficiencies
HIV main acquired immunodeficiency
->acquired SCID (affects CD4 T-cells)
Last changed10 months ago