Lecture 30: Immunodeficiencies Flashcards by Jack Wilkins

When do immunodeficiencies occur?

when one or more components of the immune system are defective

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What enables greater understanding of the molecular basis for immune function?

characterisation of where mutations occur

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What are the two categories of immunodeficiency?

inherited immunodeficiency and acquired immunodeficiency

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What is inherited immunodeficiency?

genetic mutations that result in immune system failure

often X-linked and autosomal recessive

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What is acquired immunodeficiency?

suppression of immune responses, immune cell depletion
most commonly associated with infection
also malnutrition, leukemia, chemotherapy, autoimmunity

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What is the proportion of those with inherited immunodeficiency who are male?

> 60%

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What is the major consequence of immunodeficiency?

increased susceptibility to infection -> recurrent infections / allergy / autoimmunity / cancer

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How are immunodeficiencies diagnosed?

by testing antibody in serum and lymphocyte counts in the blood

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How are immunodeficiencies treated?

antibiotics, intravenous immunoglobulin, enzyme replacement and bone marrow transplant

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What are the types of primary immunodeficiencies?

B cell and T cell deficiencies

also combined deficiencies (SCID)

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What is X-linked agammaglobulinemia caused by? What does this result in?

caused by a mutation in the gene coding for Bruton’s tyrosine kinase (Btk)
results in an inability of pre-B cells to make a complete BCR, leading to pre-B cell apoptosis

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Why does X-linked agammaglobulinemia result in immunodeficiency?

results in a block in B cell development which leads to a lack of antibody production

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How is X-linked agammaglobulinemia treated?

routine intravenous Ig therapy (weekly / monthly)

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What is hyper IgM syndrome?

family of genetic disorders associated with an absence of isotype switching (no IgG, IgA)
therefore there is a compensatory increase in IgM serum

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How is hyper IgM syndrome treated?

routine intravenous Ig therapy

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What is X-linked hyper IgM syndrome caused by?

mutations in CD40L -> defective CD40 signalling

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Where is CD40L and CD40 expressed?

CD40L: expressed on activated T cells
CD40: expressed on B cells, macrophages, DC

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What is the CD40-CD40L interaction essential for?

isotype switching, affinity maturation, memory B cell generation
macrophage activation

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What is hyper IgM syndrome type 2 / AID deficiency caused by?

a mutation in activation-induced cytidine deaminase (AID) which results in a block in isotype switching and affinity maturation

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What is the role of AID?

initiates a cascade that results in dsDNA breaks -> allows new constant region in the heavy chain to be introduced -> point mutations in variable regions (somatic hypermutation)

What is selective IgA immunodeficiency caused by?

a block in B cell differentiation into IgA-plasma cells

genetic defect is unknown

What does selective IgA immunodeficiency result in?

patients have increased susceptibility to respiratory infections (little to no IgA at mucosal surfaces)

What is common variable immunodeficiency (CVID) caused by?

defect in 1 or more genes affecting B cell growth or stimulation

What does common variable immunodeficiency result in?

present with variable reductions in IgG and IgA

varying degrees of disease (mild-recurrent infections)

What is Wiskott-Aldrich syndrome caused by?

X-linked genetic defect in WAS protein

What does Wiskott-Aldrich syndrome (T cell deficiency) result in?

induces actin polymerisation and redistribution in lymphoid cells, affecting cell movement and signalling

What is Wiskott-Aldrich syndrome characterised by?

thrombocytopenia (low platelet count), susceptibility to bruising/haemorrhage and impaired T cell function, low serum Ig levels

How does Wiskott-Aldrich syndrome affect T cell development?

there is normal T cell development (thymus), but there are decreased numbers of peripheral T cells

What is the role of WAS expressed in T cells?

plays a role in actin polymerisation and cytoskeleton reorganisation upon TCR ligation required for the formation of the immunological synapse

What is familial hemophagocytic lymphohistiocytosis (T cell deficiency)?

autosomal recessive disorder (missense mutations)

What does familial hemophagocytic lymphohistiocytosis result in?

lack of perforin in CD8+ T cells, polyclonal CD8+ T cell accumulation in lymph nodes and uncontrolled T cell activation, cytokine storm

What does epidermodysplasia verruciformis (T cell deficiency) result in?

abnormal susceptibility to cutaneous HPV infection and defective T cell immunity

What is epidermodysplasia verruciformis (T cell deficiency) caused by?

mutations in EVER1, EVER2 genes | involved in the regulation of zinc homeostasis in lymphocytes

What is DiGeorges syndrome caused by?

deletion of genes from chromosome 22 which can occur randomly rarely inherited and present from birth

What are the symptoms of DiGeorges syndrome?

congenital heart disease, facial abnormalities, cleft palate, learning difficulties, frequent infections (defect in T cell maturation)

What can a mutation in Tbx1 result in?

a failure of thymic epithelium development during embryogenesis

What is bare lymphocyte syndrome II caused by?

``` mutations in any one of four genes that control expression of MHC class II genes -> class II transactivator (CIITA), RFXANK, RFX5, RFXAP ```

What does bare lymphocyte syndrome II result in?

little or no MHC class II expression on surface of B cells, macrophages or dendritic cells

What is the consequence of no MHC II expression?

failed positive selection in the thymus -> reduced helper T | cells, reduced antigen presentation

What is severe combined immunodeficiency (SCID) caused by?

defect in >14 genes which results in profound deficiencies in B, T and NK cell function

What is the only current treatment for severe combined immunodeficiency (SCID)?

bone marrow transplant

What is X-linked SCID caused by?

mutation in common g-chain (CD132) which is present in several cytokine receptors

What does X-linked SCID result in?

absence of functional B, T and NK cells | infants suffer increased susceptibility to array of opportunistic infections

What genes are mutated on autosomal chromosomes in autosomal recessive SCID?

JAK3 (tyrosine kinase), adenosine deaminase (ADA) and recombinase activating genes (RAG)

What is JAK3?

a tyrosine kinase that mediates downstream signalling after cytokines bind g-chain receptor

What is autosomal recessive SCID (ADA) caused by?

defect in adenosine deaminase (ADA) enzyme

What is ADA required for? What happens when there is a defect in this enzyme?

breakdown of purines defect results in accumulation of toxic intermediates (deoxyadenosine) -> destruction of lymphocytes and progressive lymphopenia

What is autosomal recessive SCID (RAG) caused by? What happens when there is a defect in this enzyme?

defect in RAG genes result in a complete lack of mature B and T cells NK cells are not affected

What are recombinase activating genes required for?

VDJ recombination in developing lymphocytes