• increase susceptibility to infections
• increase risk of autoimmune disease
• increase risk of certain kinds of cancer
  • lymphomas
  • EBV induced lymphoproliferative disorders

• adaptive
  • defect in lymphocyte activation/ maturation
• innate
  • defect in production/maturation
  • defect in activity

• history
  • type/frequency of illness
  • family history
• physical exam
  • associated abnormalities
  • lymphoid tissue
• lab screening
  • CBC, differential
  • IgA, IgG, IgM, IgE levels
  • baseline Ab titers

Immune state of infants for the first few months of life

• relatively immunosuppressed (doesnt mean they got immunodeficiency)
• infant gets IgG from mom
• so intrinisic IgG, IgA relatively suppressed
• normal B cell levels
• delay maturation of Th cell function
• resolve by 12-18 months

• cause- B cell deficiency secondary to lack of T cell response
• life threatening infection in the first 1-2 years of life

• X linked (ex: JAK deficiency, IL-7 receptor deficiency, gama chain of IL-2 R deficiency)
• Rag deficiency
• Adenosine deaminase deficiency

Most likely cause of X linked SCID

• mature T cells carry normal gene
• lymphocytes with abnormal gene fail to mature
• non lymphoid cells with random X inactivation

• marked decrease in T cell numbers
• marked decrease in NK cell number (IL-15 R deficiency)
• often normal B cell numnbers
• decreased Ig's

Pathology of JAK3 kinase

• identical phenotype as X linked SCID cause IL-7 usies Jak3 signal

• progressive decrease of B and T cells
• T cells poorly responsive
• severe lymphopenia
• decrease IgG

• normally ADA function to salvage pathway of purine degredation
• if deficient, accumulate deoxyadenosine and dATP
  • inhibit DNA syn.
  • lymphocytes very sensivite to this effect

Pathology and effect of PNP SCID

• cause- involved in purine catabolism, so if deficient, get accumulation of deoxyG and dGTP
• clinical signs
  • normal B cells
  • normal or decrease IgG
  • progressive secrease in T cells

• cause- defect at level of hematopoietic cell leads to defective maturation of B, T and myeloid cells
• signs
  • marked decrease in B and T cells
• inheritance- autosomal recessive

• cant make Ag R's because you do not have genetic recombination, so lack mature B and T cells
• inheitance- autosomal recessive

• associated with Th2 allergioc type inflammatory syndrome
• few T cells present have restricted TCR repertoire and expand and differentiate

• genetic cause- deletion in 22q
• cause- failure of 3rd, 4th pharyngeal pouch development
• clinical signs
  • thymic hypoplasia/aplasia
  • hyperparathyroidism
  • cardiac outflow malformations
  • facial deformities

• normal or decrease Ig
• normal B cells
• T cell function may improve with age, but generally decrease T cell number and function

• decrease of all isotypes of IgG
• marked decrease B cell numbers
• absence of germinal centers in lymph node
• absense of plasma cells in tissue
• T cells generally normal

• cause 
  • defect in B cell Tyr kinase
  • intrinsic defect of pre-B to mature B cell differentiations
• inheritance: X linked
• clinical symptoms
  • recurrence of sinopulmonary bacterial infections
  • autoimmune disorders in 20% of patients

Clinical signs and inheritance of IgA deficiency

• clinical signs
  • IgA1 and IgA2 decreased
  • normal B cell numbers
• inheritance- autosomal recessive
• underlyin defect unclear

• clincal sign 
  • decrease in one or more isotypes
  • defect in B cell differentiation
• usually in children: IgG2/G4 oftn more common with IgA deficiency
• adults: IgG1/G3 type deficiency

Defect of X linked hyper IgM syndrome

• defect: most commonly T cells lack CD40 ligand (absence of switch signal)
  • associated defect in cell mediated immunity (CD40L involved in macrophage activation)
  • associated with autoimmunity)
• clinical sign- IgM normal/increased
• appearance of lymph node
  • effaced architecture
  • absence of germinal center

• decreased IgG, IgM, IgA
• impaired Ab response to vaccines/infections
• normal or decreased B cell numbers
• normal T cell numbers

• associated with:
  • autoimmunity
  • immune thrombocytopenic purpura
  • hemolytic anemai
  • alopecia
  • thyroiditis
• onset: early childhood of adulthood
• genetic- some cases of association with ICOS deficiency

• genetic cause- X linked defect in SAP adaptor protein
• clinical signs
  • abnormal response to Epstein Barr virus (very severe disease)
  • uncontrolled CD8 T cell prolif.
  • uncontrolled hemophagocytosis
  • uncontrolled B cell proliferation (seconday to EBV transformatoin) and associated with B cell lymphomas
  • defects in germinal center formation and Ab production

• activates a family of molecules called SLAM
  • involved in NK cell/T cell activation
  • involved in T cell help in germinal centers

Familial hemophagocytic syndrome (cause, clinical signs, genetic cause)

• cause- inappropriate, ineffective T cell activation
• clinical signs
  • increase hemophag. activity lead to pancytopenias
• genetic cause- associated with mutation in perforrin gene (also cases with mutations affecting small G protein regulation or granule exocytosis)

Job's syndrome (hyper IgE syndrome)

• clinical signs
  • dermititis
  • recurrent staph abscesses
  • cyst forming pneumonia
  • elevated IgE in serum
  • defect response IL-6 and IL-10 (defect in Th17)
• genetic cause-autosomal dominant mutation of STAT3
• mutlisystem disorder
  • defect in immune system regulation and cell mediated immunity (Th17, neutrophil function)
  • defect in IL-6, 10

• inheritance- X linked of WASP protein
• clicical signs
  • thrombocytopenias
  • eczema
  • malignancies
  • progressive T cell decline in number function
  • cant produce antibodies to T cell independent polysacc. Ag

• cytoplasmic protein in bone marrow derived cells
• interact with adapter molecules and small G proteins
• regulate actin polymerization, change shape and motility

• interfere with trafficking of leukocytes to sites of inflammation and cell to cell interaction
• also defects in lymphocyte activation

• inheritance: autosomal recessive at ATM gene at chromosome 11
• pathology: defect in DNA repair
• clinical signs
  • decrease IgA and IgG2
  • decrease T cell numbers

Different types if innate immunity deficiencies

• defects in interaction with adaptive immune system
• defect in microbial activities in phagocytes
• defect in NK cells and other leukocytes
• complement deficiencies

• nutropenia
• disorders of oxidant metabolsim
  • chronic granulomatosis disease
  • myeloperoxidase deficiency
• disorders of nonoxidant metabolism
  • specific granule deficiency
  • Chediak Higashi syndrome
  • leukocyte adhesion deficiency

• inherited disorder of NADPH oxidase complex
• leads to defective generation of oxidant superoxide anion and its metabolites
• clincial defects
  • recurrent, life threatening intracellular bacterial and fungal infection
  • exhuberant inflammatory reactions leading to granulomas

genetics of leukocyte adhesion disorder

• genetics- autosomal recessive defect causing lack of mobility, chemotaxis, adherence, endocytosis
• clinical consequences
  • recurrent bacterial and fungal infection
  • delayed wound healing
  • chronic leukocytosis
  • defective margination, diapedesis, migration
• cause- absence/decrease of expression of beta2 cells involving CD18

• genetics- autosomal recessive defect
• clinical signs
  • recurrent infection (pyogenic bacteria)
  • partial oculocutaneous albinism
  • organomegaly
  • cytophagocytosis
• immune effect- giant granules in monocytes, neutrophils, NK cells
• defect in adherence and killing