Primary Immunodeficiencies

Question 1

Deficiency of humoral immunity

Answer 1

Encapsulated, pus forming bacteria and some viruses

Question 2

Deficiency of cell mediated immunity

Answer 2

viruses and other intracellular microbes

Question 3

Chronic granulomatous disease (INNATE)

Answer 3

• X linked or autosomal recessive
• Caused by mutations in component of the phagocyte oxidase enzyme–> defective phagocytosis
• Recurrent infections with intracellular fungi and bacteria, such as staph, enterobacteria, and gram negative organisms from early childhood
• Infections of Nocardia and mycobacteria of special importance
• Organisms that produce catalase are particularly problematic
• Invasive infection with aspergillus is leading cause of death

Question 4

Test for CGD

Answer 4

• Neutrophil function testing
• Direct measurement of super oxide production
• Cytochrome C reduction assay
• NBT reduction test
• DHR oxidation test

Question 5

What disease are mothers of x linked forms of CGD at increased risk of ?

Answer 5

• Lupus

Question 6

Chediak Higashi (INNATE)

Answer 6

• Autosomal recessive
• Defect in intracellular lysosome trafficking
• Recurrent infections with pyogenic bacteria
• Partial oculocutaneous albinism
• Nerve defects
• Bleeding disorders

Question 7

C1 deficiency

Answer 7

• Very severe, early onset SLE

Question 8

C1 esterase inhibitor deficiency

Answer 8

• Inhibitor stops activation by the classical pathway
• Deficiency causes increased classical pathway activation–> plus increased bradykinin–> Hereditary angioneurotic edema (HANE)
• Autosomal dominant
• Clinical manifestations include intermittent acute edema of skin and mucosa–> abdominal pain, vomiting, diarrhea, and life threatening airway obstruction
• Some patients have SLE-like syndrome

Question 9

Labs associated with C1 esterase inhibitor deficiency

Answer 9

• Low C1 inhibitor level and function
• Low C4
• Normal C1q

Question 10

C2 def

Answer 10

• Most common
• Freq of heterozygous state in the population is 1%
• Associated with lupus but not typically increased infections

Question 11

C4 def

Answer 11

• Autosomal recessive

- Associated with lupus but not typically increased infections

Question 12

C5-9

Answer 12

• Disseminated neisseria infections, including meningitis and gonorrhea

Question 13

Leukocyte adhesion deficiencies

Answer 13

• Autosomal recessive disorders
• Severe peridonititis and other recurrent bacterial and fungal infections starting early in life
• Inability to make pus
• Impaired wound healing

Question 14

LAD-1

Answer 14

• Caused by mutations in the beta chain (CD18) of beta 2 integrins
• Leuk functions are defective–> adherence to endothelium, neutrophil aggregation and chemotaxis, phagocytosis, cytotoxicity mediated by neutrophils, NK cells and T lymphocytes

Question 15

X linked SCID

Answer 15

• Due to mutations in gene for the common gamma chains for cytokines
• Reduced numbers of mature NK and T cells
• Normal or increased B cell with decreased humoral immunity
• Severe life threatening infections with bacteria and viruses
• Chronic GI infections lead to diarrhea and malabsorption
• Infections from live attenuated vaccines

Question 16

Pathogenesis of chronic skin rash in X linked SCID

Answer 16

• Graft versus host reaction

- Maternal T cells enter fetus, not rejected and react against fetal tissues

Question 17

Adenosine deaminase def

Answer 17

• Autosomal recessive

- Results in decreased counts of both T and B cells

Question 18

X linked agammaglobulinemia (Bruton tyrosine kinase)

Answer 18

• X linked mutations or deletions in gene encoding Bruton TK
• Results in failure of B cells to mature beyond pre B cell stage in bone marrow
• Decreased oral and serum Ig Isotypes and reduced B cell numbers
• T cells normal
• Boys are susceptible to chronic enteroviral infections, including vaccine strain poliomyelitis

Question 19

Common variable immunodeficiency (CVID)

Answer 19

• Reduced serum levels of Ig
• Impaired antibody responses to infection and vaccines
• Increased incidence of infections (h Flu and strep pneumo)
• Association with other autoimmune diseases -> Pernicous anemia, atrophic gastritis, hemolytic anemia, Evans, IBD, lymphoid interstitial PNA, JIA
• High incidence of malignant tumors, particularly lymphomas

Question 20

X linked hyper IgM

Answer 20

• Mutations in gene encoding T cell effector molecule CD40 ligand
• Does not bind to CD40 and therefore does not stimulate B cells to undergo heavy chain isotype switching
• Also see defection activation of macrophages and DCs
• Increased infections with bacteria and intracellular pathogens including PCP

Question 21

Di george

Answer 21

• Caused by anomalous development of 3rd nad 4th branchial pouches leading to thymic hypoplasia
• Decreased T cells, normal B cells and normal or decreased serum IG concentrations
• T cell function tends to improve with age and is often normal by age 5

Question 22

X linked lymphproliferative disease

Answer 22

• Unable to eliminate EBV
• Fulminant mono
• Development of B cell tumors

Question 23

Bare Lymphocyte syndrome (Class II MHC def)

Answer 23

• Class II MHC def
• Patients express little or no HLA-DP, DQ, DR on B lymphocytes, macrophages and DCs
• Also fail to express MHC II in response to interferon gamma
• Leads to failure of APCs to activate CD4 lymphs and defection positive selection of CD4 lymphs
• Deficient delayed type hypersensitivity responses and antibody responses to T cell dependent protein antigens
• Usually appears in year 1 and fatal unless BMT

Question 24

Class I MHC deficiency

Answer 24

• Caused by mutation in TAP (transporter associated with antigen processing complex) which normally transports peptides from the cytosol to the ER where they are loaded into class I MHC
• leads to decreased CD8 t cells and function
• Suffer from resp tract infections and necrotizing granulomatous skin lesions
• NOT usually viral infections

Question 25

Wiskott Aldrich

Answer 25

• X linked
• Bacterial infections, Eczema, low platelets
• T cells may be normal in the beginning but lymphocytes reduce with age
• Infections with encapsulated bacteria

Question 26

Ataxia Telangiectasia

Answer 26

• Autosomal recessive
• Abnormal gait, vascular malformations, neurologic deficits, increased incidence of tumors, immunodeficiency
• Upper and lower resp tract, bacterial infections, autoimmune phenomena
• Increasing frequency of cancer with advancing age

Question 27

Autoimmune lymphoproliferative syndrome (ALPS)

Answer 27

• Defective lymphocyte apoptosis due to FAS or FAS ligand mutation
• LAD, splenomegaly, +/- hepatomegaly
• Autoimmunity–> cytopenias, nephritis, hepatitis, guillian barre, uveitis
• Increased risk of lymphoma

Question 28

Hemophagocytic syndrome

Answer 28

• NL and CTLs are defective in their ability to kill infected cells but respond strongly to persistent microbes by secreting interferon gamma
• Leads to MAS

Question 29

IPEX

Answer 29

Immune dysregulation, polyendocrinopathy, enteropathy, X linked

• Def of T regs
• Cytopenias, renal disease, dev delay, pulmonary disease

Question 30

Apeced

Answer 30

• Autoimmune polyendocrinopathy candiasis ectoderma dystrophy
• Cutaneo-mucus candiasis, hypoparathyroidism and addison’s disease
• Due to defect in negative selection of T cells

Question 31

Interferon gamma receptor mutations lead to intracellular infections of what…

Answer 31

mycobacteria and salmonella