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Flashcards in Clinical Disease Deck (31):

NEMO deficiency

• 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


X-linked lymphoproliferative syndrome

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


Leukocyte adhesion deficiency-I

• 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


Chronic granulomatous disease

• 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


Chediak-Higashi Syndrome

• 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


Properdin deficiency X-linked

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


C3 deficiency

• 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


Deficiency in C5-9

Susceptibility to Neisserial inefctions


Paroxysmal nocturnal hemoglobinuria

• 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


Hereditary angioedema

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


Bare lymphocyte syndrome II

• 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)


Bare lymphocyte syndrome I

• 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


Autoimmune diseases

• 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



• 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


Omenn syndrome

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


AIRE deficiency

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


X-linked agammaglobulinemia

• 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


γ chain deficiency (X-linked SCID)

• 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


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

• 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


CD40L deficiency

• 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


AID deficiency

• 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


Job syndrome (hyper IgE)

• 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


Duchenne muscular dystrophy (and Becker)

• 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



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


Cancer diagnosis

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



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



• 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.


Ehler-Danlos syndrome (rubber man syndrome)

• 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.


Osteogenesis imperfecta (brittle bone syndrome)

• 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.


Marfan syndrome

• Mutation of fibrillin gene
• People with Marfan are tall and thin with long arms, legs, fingers, and toes


alpha-1 antitrypsin deficiency

• 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.