Hereditary immune deficiency diseases

Question 1

Immune deficiency disorders

Answer 1

• Characterized by recurring infection, with an increased susceptibility to cancer or autoimmunity (onset at any age)
• Primary immune deficiency (ID): genetic mutations that induced immunocompromise (IC)
• Secondary ID: acquired (extrinsic), or factor induced IC due to infections, malnutrition, dugs/radiation
• Natural ID: normal developmental processes of IC (newborns and geriatrics)

Question 2

Granulocyte (PMN) deficiencies

Answer 2

• Skin, lymph node, deep tissue infections with staph, GN bacterial, aspergillus/candida
• May show hepatosplenomegaly/lymphadenopathy
• Due to neutropenia
• Underlying genetic deficiency could be chronic granulomatous disease
• Deficiency in innate immunity

Question 3

Chronic granulomatous disease (CGD)

Answer 3

• Usually (60%) X linked recessive, onset generally in 1st year of life
• Recurrent infections of staph, GN, fungi
• Have normal neutrophil morphology, phagocytosis, chemotaxis
• Phagocytes deficient in NADPH oxidase gene (Phox), leads to inability to destroy phagocytosed pathogens
• Dx: assessment of Phox activity via NBT test

Question 4

Hyposplenism

Answer 4

• Can be primary congenital or secondary to various ID diseases (such as SCID), deficiency in innate immunity
• Have recurrent bacterial sepsis due to S pneumo and H influenzae
• Both of these bacteria require Ab opsonization
• Normally within hours of infection B cells in spleen will produce IgM Abs against these organisms
• Without these Abs the organisms are able to rapidly proliferate

Question 5

Deficiencies in adaptive immune system

Answer 5

• Defects in lymphocyte maturation

- Defects in lymphocyte signaling and effector functions

Question 6

DiGeorge phenotype

Answer 6

• Recurrent opportunistic infections of viruses, fungi, and mycobacteria
• Often have infections in GI, thrush, dermatitis (epithelial barriers), also have hepatosplenomegaly and lymphadenopathy
• Mechanisms of ID: multiple mutations in T cell maturation and signaling pathways, deficient T cell mediated immune response, deficient help for B cells to mature

Question 7

DiGeorge syndrome

Answer 7

• Autosomal dominant trait that has varying degrees of deficiency (some are asymptomatic, some have no T cells at all)
• Characterized by lack of functioning thymus, and therefore severe T cell deficiency
• Other malformations may exist: craniofacial, cardiovascular, parathyroid (hypocalcemia)
• Deletion on chrom 22

Question 8

SCID: severe combined immune deficiency

Answer 8

• Characterized by recurrent infections that reflect combined dysfunction of T and B cells
• Defects primarily affecting T cells: complete DiGeorge syndrome (absent thymus), gc-deficiency (IL2/7 dysfunction preventing development of T cells from stem cells, X linked SCID)
• Signaling defects: ineffective TCR function
• Every newborn in CA is screened for SCID
• Common feature of most SCID: largely decreased T cell count, normal B cell/NK cell number (but decreased B cell function due to lack of CD4s)

Question 9

Phenotypes of B cell deficiencies

Answer 9

• U and L RT infections (IgA/IgG, respectively), GI infections (IgA)
• Can be from multiple mutations in B cell maturation and signaling, or deficient Ag-specific Ab required for efficient opsonization of encapsulated organisms (may be systemic or local)

Question 10

Selective IgA deficiency

Answer 10

• Most common primary immune deficiency, variable genetic patterns
• Most likely a signaling defect resulting in failure of isotype switch to IgA
• Undetectable IgA in serum
• Broad clinical spectrum (possible compensation): asymptomatic, atopic disease, recurrent infections, autoimmune disorders (AID)

Question 11

X linked agammaglobulinemia

Answer 11

• X linked genetic defect in B cell maturation, due to mutation in bruton tyrosine kinase (BTK)
• This blocks the B cell maturation beyond pre-B cells
• Absent mature B cells, absent IgM/IgG/IgA
• Normal T cell number and function

Question 12

Common variable immune deficiency (CVID)

Answer 12

• Variable clinical features: Ig’s affected, age of onset, degree of T cell abnormalities, genetic mutations
• Have recurrent bacterial infections, hypogammaglobulinemia, impaired Ag-specific Ab responses, but have normal number of B cells

Question 13

Rx of immune deficiency disorders

Answer 13

• Correct secondary pathology (infection, malnutrition)
• Enhance support of existing immune responses: INFg (CGD), hematopoietic GFs (neutropenia), ILs
• Replacement of missing/dysfunctional factors: BM/SC transplant, IVIG
• Correction of primary genetic defect via gene therapy: X linked SCID, CGD, ect

Question 14

T cell receptor excision circles (TREC)

Answer 14

• Small circles of T cell DNA, by products of TCR genetic rearrangement during generation of Ag-specific TCR in thymus
• They are stable, detectable, and quantifiable
• Are a surrogate for # of T cells in body

Question 15

T cell subset analysis

Answer 15

• Specific CDs (cluster of differentiation) are what define each subset of T cells
• These can be measured by flow cytometry and Ag-specific monoclonal Abs
• TREC + flow cytometry allow us to distinguish what type of SCID a child has
• SCID is fatal but can be cured w/ timely HSC/BM transplant (only done once SCID is detected via screening)

Question 16

T cell dysregulation in CVID

Answer 16

• Able to switch from IgM->IgE but not IgM->IgG or IgA means T cell dysregulation
• Chronic respiratory infections means B cell/Ab deficiency
• AID means T cell dysregulation
• Rx of B cell/Ab deficiency is IVIG (IgG only)
• Some features of CVID: T cell dysregulation, Ab deficiency (but w/ normal # of B cells)