Clinical Disease

Question 1

NEMO deficiency

Answer 1

• Failure to activate the NF- κB pathway due to deficiency in IKBKG gene (NEMO)
• Elevated IgA or IgM; other Igs low
• Susceptibility to pyogenic infections and mycobacterial infections
• Patients with ED (ectodermal dysplasia) have thickened skin, conical teeth, absence of sweat glands, and thin, sparse hair
• No response to pneumococcal vaccines

Question 2

X-linked lymphoproliferative syndrome

Answer 2

• Mutation in SH2D1A gene affects NK signaling
• Killing activity is impair; high lymphocyte proliferation
• Increased susceptibility to EBV infections

Question 3

Leukocyte adhesion deficiency-I

Answer 3

• Deficiency in the CD18 gene, which encodes the β subunit of the LFA-1 and Mac-1 integrins, and CR3 and CR4 complement receptors
• Leukocytes have impaired migration and impaired phagocytosis
• No pus formation
• Susceptible to pyogenic bacterial infections early in life
• Delayed umbilical cord separation and omphalitis, destructive periodontitis, leukocytosis

Question 4

Chronic granulomatous disease

Answer 4

• Component of oxidative burst pathway is deficient (NADPH Oxidase)
• Impaired microbial killing
• Recurrent catalase-positive bacteria and fungal infection
• Granuloma formation due to dysregulated inflammatory response

Question 5

Chediak-Higashi Syndrome

Answer 5

• A lysosomal trafficking regulator protein (LYST) is deficient
• Lysosome fusion is abnormal, reducing phagocytic functions in phagocytes and lymphocytes
• Lymphoproliferation in organs; giant lysosomes in phagocytes
• Symptoms: Recurrent infections with pyogenic bacteria, partial oculocutaneous albinism, neuropathy, and bleeding

Question 6

Properdin deficiency X-linked

Answer 6

• Properdin functions to stabilize the C3 convertase complex in the alternative pathway
• Increased susceptibility to meningococcal infection (Neisseria meningitides)

Question 7

C3 deficiency

Answer 7

• Most serious of the complement immunodeficiencies
• Recurrent, severe infections with encapsulated bacteria leading to high mortality
• If patient survives infections, immune-complex-mediated glomerulonephritis may result

Question 8

Deficiency in C5-9

Answer 8

Susceptibility to Neisserial inefctions

Question 9

Paroxysmal nocturnal hemoglobinuria

Answer 9

• Deficiency in the PIGA gene, which encodes an enzyme involved in GPI (glycophosphatidylinositol)-anchor production
• DAF and CD59 utilize this anchor and if defective, cannot associate with the host cell membrane
• Erythrocytes targeted for MAC-mediated lysis and abnormal platelets
• Symptoms: Dark morning urine, intravascular hemolytic anemia, and susceptibility to deep vein thrombosis

Question 10

Hereditary angioedema

Answer 10

• C1 INH also regulates bradykinin production, so without it, massive edema results
• Note: Edema was originally attributed to C2 kinin

Question 11

Bare lymphocyte syndrome II

Answer 11

• Genes associated with MHCII are deficient
• No selection of CD4+ T cells in thymus, so no CD4+ T cells at all
• Low immunoglobulin (no class switching)
• SCID-phenotype (more severe than type I)

Question 12

Bare lymphocyte syndrome I

Answer 12

• TAP, tapasin, beta2 microglobulin deficiency
• No selection of CD8+ T cells in thymus, so no CD8+ cells
• Symptoms can present from asymptomatic to recurring lower respiratory tract infections

Question 13

Autoimmune diseases

Answer 13

• Certain autoimmune diseases have been linked to a certain MHC gene, indicating genetic predisposition
o Systemic lupus erythematous – DR2/DR3
o MS – DR2
o Reactive arthritis – B27

Question 14

SCID-RAG1/2

Answer 14

• RAG1 or RAG2 genes are deficient
• No V(D)J (somatic) recombination – no B and no T cells, no thymic shadow
• Failure to thrive early in life; high susceptibility to infection
• ARTEMIS deficiency similar to RAG1/2 deficiency

Question 15

Omenn syndrome

Answer 15

• Missense mutation in RAG1 or RAG2 genes – impaired activity
• Symptoms depend on the activity of RAG; susceptibility to infection, autoimmunity

Question 16

AIRE deficiency

Answer 16

• Causes autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
• T cells undergo limited selection and recognize self antigen

Question 17

X-linked agammaglobulinemia

Answer 17

• Deficiency in the BTK (Bruton tyrosine kinase) gene
• Deficient BTK prevents BCR signaling, which prevents selection during B cell development
• No B cells or Igs produced
• Recurrent pyogenic infections
• Susceptibility to encapsulated bacterial infections

Question 18

γ chain deficiency (X-linked SCID)

Answer 18

• The IL2RG gene, encoding the IL-2Rγ chain, is defective
• No T cells, no NK cells, no B cell activation, no thymic shadow
• Symptoms: thrombocytopenia, failure to thrive, severe infections
• Mutation in JAK3 = same symptoms

Question 19

Mycobacterial infections (M. tuberculosis, M. leprae) – Th1 and Th2

Answer 19

• Mycobacterium are intracellular pathogens that replicate in MΦ by preventing phagolysosomal fusion
• Th1 cells induce phagolysosomal killing of Mycobacterium and promotes granuloma formation (limits spread)
• Individuals with poor Th1 (high Th2) responses are susceptible to aggressive disseminated Mycobacterial disease

Question 20

CD40L deficiency

Answer 20

• Deficiency of the CD40L gene, an X-linked hyper IgM syndrome
• Costimulation of B cells is defective – no Ig isotype switching
• Macrophage activation is defective
• Symptoms: recurrent infections with pyogenic bacteria

Question 21

AID deficiency

Answer 21

• Deficiency of the AID gene; a hyper IgM syndrome
• Without functional AID, somatic hypermutation and class switching does not occur
• Symptoms: Susceptible to pyogenic infections

Question 22

Job syndrome (hyper IgE)

Answer 22

• Deficiency of the STAT3 transcription factor, which leads to deficient Th17 development
• Susceptibility to cutaneous fungal and bacterial pathogens; chronic mucocutaneous candidiasis
• Symptoms: Skin abscess

Question 23

Duchenne muscular dystrophy (and Becker)

Answer 23

• Mutation of X-linked dystrophin gene
• Dystrophin forms striated muscle networks; mutation results in damage to membranes due to repeated buckling, leads to muscular degeneration

Question 24

Chemotherapy

Answer 24

• Chemicals that interfere with microtubular assemble preferentially attack tumor cells because these rapidly dividing cells require microtubules for cell cycle progression

Question 25

Cancer diagnosis

Answer 25

• Intermediate filament antibodies in the core are used to identify the origin of tumor cells, which often lose other distinguishing characteristics.

Question 26

Fibrosis

Answer 26

• Excessive collagen production (e.g. pulmonary fibrosis, atherosclerosis, and scar tissue in liver due to over consumption of alcohol).

Question 27

Scurvy

Answer 27

• Lack of hydroxyproline residues due to dietary deficiency of vitamin C. Symptoms include weak and malformed bones, teeth, skin, blood vessel walls, and dermal hemorrhaging.

Question 28

Ehler-Danlos syndrome (rubber man syndrome)

Answer 28

• Mutations resulting in underproduction or incomplete processing of different collagens. Symptoms range from loose skin and joints, to neonatal death. Contortionists often have this disorder.

Question 29

Osteogenesis imperfecta (brittle bone syndrome)

Answer 29

• Mutations of type I collagen, which interfere with triple helix assembly (e.g. substitution of glycines residues with bulkier amino acids). The most severe mutations result in lethality in utero or soon after birth. Less severe mutations produce brittle bones. Note, due to the numerous fractures observed in children with this disorder, it can easily be misdiagnosed as child abuse.

Question 30

Marfan syndrome

Answer 30

• Mutation of fibrillin gene

* People with Marfan are tall and thin with long arms, legs, fingers, and toes

Question 31

alpha-1 antitrypsin deficiency

Answer 31

• 1-antitrypsin is an inhibitor of various proteases such as elastase. Homozygous 1-AT mutants are predisposed to emphysema because the elastin in their alveolar walls is degraded.