Immunodeficiencies

most relevant system to study the function of a gene

observe the phenotype

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

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

many deficiencies at different stages of B-&T-cell development

IL-2/-4/-7/-9/-15/-21 share a common γ chain that is coded on the X chromosome

impaired cytokine signaling

inactivated common ß-chain

signaling of cytokines affected

needed for T-cell maturation & T-cell help for B-cells

JAK needed for maturation

->SCID

the mutation prevents maturation to pro-T-cell

no TCR rearrangement

no TCR+ T-cells

enzymes involved in DNA rearrangement

TCR & BCR rearrangement

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

MHC class II deficiency

TF necessary to produce MHCII -> not possible to select CD4+ T-cells

SCID as no B-cell collaboration is possible

impaired CD3 signaling -> impairs pro-T-cell to pre-T-cell transition

pre-TCR to double-positive T-cell transition impaired

SCID-like immunodeficiency (tyrosine kinase in signaling involved)

impairs maturation from double-positive T-cell to CD8+ T-cell

transport & loading of peptides affected

MHC class I deficiency

no positive selection-> no SCID as the humoral response is not affected

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

B-cell deficiency (equivalent to CD3)

no SCID -> only humoral response affected

pro -> pre-B-cell

B-cell deficiency

involved in the first signaling

total B-cell deficiency

pre-B-cell to immature B-cell transition

X-linked agammaglobulinemia

B-cell specific -> involved in B-cell maturation

reduces the possibility of producing IgG (γ-globulin)

problem in class switch

common γ-chain

TCR/BCR generation

ADA

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

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

less severe

B-cell deficiency (partial)

defect in immunoglobulin production but usually not all isotypes are affected

heterogenous group of disorders

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

hyper-IgM syndromes

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

unknown mutated genes

1 specific isotype can’t be produced

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

almost everything can be inactivated

inactivation in many different genes -> system not redundant

associated with susceptibility to certain infections & accumulation of immune complexes

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

new T-&B-cells with the correct gene

but graft vs. host disease

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

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

HIV main acquired immunodeficiency

->acquired SCID (affects CD4 T-cells)