Biochem to Immuno, plus Pathophys

Question 0

Pt with muscle weakness - difficulty rising from chairs and combing hair, MHC I overexpression on sarcolemma and CD8 infiltration on muscle biopsy?

Answer 0

Polymyositis

symmetric progressive proximal muscle weakness

Question 1

Short pt with disproportionately short limbs and large head? Mutation? Inheritance?

Answer 1

Achondroplasia - most cases occur sporadically, but autosomal dominant

Mutation in fibroblast growth factor receptor 3 (FGFR3), which inhibits chondrocyte proliferation and differentiation leading to impaired cartilage maturation and thus impaired endochondral/cartilage-mediated ossification (found in the epiphyseal growth plates of long bones)

Intramembranous/non-cartilage-mediated ossification is normal.

Question 2

What is fibrillin and where is it found? What disorder is it defective in? Inheritance?

Answer 2

extracellular glycoprotein
major component of microfibrils that forms a sheath around elastin fibers
Fibrin in the extracellular space acts as a scaffold for deposition of elastin extruded from connective tissue cells.

microfibrils present in blood vessels/aortic media, periosteum, and suspensory ligaments of the lens

Marfan syndrome
Defective fibrillin-1 gene
Autosomal dominant

Question 3

34yo pt with mild urethritis that resolves spontaneously, negative for gonococcal infection - weeks later, acute conjuctivitis, right knee pain, vesicular rash on palms and soles?

Answer 3

Reactive arthritis

will also likely have sacroiliitis

Question 4

Case fatality rate for an infection - how calculated?

Answer 4

number of fatal cases divided by the total number of people with the disease

Question 5

Pt with tiredness and a mediastinal mass on imaging? What disease and mechanism?

Answer 5

Myasthenia gravis
circulating antibodies against cell surface ACh receptor results in binding and complement-mediated destruction, producing weakness (most commonly in extraocular muscles)

Associated with thymoma or thymic hyperplasia

Question 6

Are specificity and sensitivity influenced by disease prevalence? What about PPV and NPV? What relationship?

Answer 6

Specificity and sensitivity are NOT influenced by disease prevalence

PPV varies DIRECTLY with prevalence and pretest probability
(high prevalence/pretest prob. = high PPV)

NPV varies INDIRECTLY with prevalence and pretest probability
(high prevalence/pretest prob. = low NPV)

Question 7

Pt taking TMP-SMX with joint pain, itchy rash, and fibrinoid necrosis and neutrophil infiltration in arteries and small arterioles?

Answer 7

Serum sickness - Type III hypersensitivity

circulating antigen-IgG complexes activate complement to attract neutrophils which release lysosomal enzymes (tissue damage)

Would find hypocomplementemia 5-10 days after antigen exposure

Question 8

What is heteroplasmy?

Answer 8

coexistence of both mutated and WT versions of mitochondrial genomes in an individual cell

Question 9

Pt with neuromuscular lesions, lactic acidosis, and ragged red skeletal muscle fibers? What is the defect? Inheritence?

Answer 9

Mitochondrial myopathies
failure of oxidative phosphorylation leads to myopathy, lactic acidosis, and CNS disease

Muscle biopsy = “ragged red fibers”

Mitochondrial inheritance - variable expression due to heteroplasmy (coexistence of both mutated and WT mtDNA in a cell)

Question 10

Pt with history of joint pain, swelling, stiffness, and subcutaneous nodules at elbow? What serum findings?

Answer 10

Rheumatoid arthritis

anti-IgG antibody (IgM)

Question 11

Calcium, phosphate, and PTH levels in pts with osteoporosis? Common fracture that results? What are the two types?

Answer 11

NORMAL lab values and normal bone mineralization
Vertebral crush fractures often occur as a results (back pain, loss of height, kyphosis)

Type I: postmenopausal (increased bone reabsorption due to low estrogen)
Type II: senile (men and women over 70yo)

Question 12

Describe the steps of collagen synthesis - which steps occur outside the cell? Name three diseases that result from defects in collagen production and the relevant step.

Answer 12

1. Synthesis (collagen alpha chains: Gly-X-Y)
2. Hydroxylation (OH on proline and lysine) **Vitamin C/scurvy
3. Glycosylation & Triple Helix formation (sugar on OH-lysine and triple helix formation via H and disulfide bonds) **Osteogenesis imperfecta
4. Exocytosis (into ECM)
   - –outside of cell—
5. Proteolytic processing (N and C terminal regions cleaved to form insoluble tropocollagen)
6. Cross-linking (covalent Lys-LysOH cross-linkage by lysyl oxidase forming collagen fibrils) **Ehlers-Danlos

VitC - problem with hydroxylation
Osteogenesis imperfecta - problem with triple helix formation
Ehlers-Danlos - problem with cross-linking tropocollagen into collagen fibrils

Question 13

What are osteoblasts derived from? What are osteoclasts derived from?

Answer 13

Osteoblasts - differentiate from mesenchymal stem cells in periosteum

Osteoclasts - differentiate from monocytes/macrophages

Question 14

Describe the pathway of osteoclast differentiation/maturation.

Answer 14

RANK-ligand expressed on surface of osteoblasts binds RANK receptor on osteoclasts to activate and induce differentiation.
OPG (soluble decoy receptor) also made by blasts - the more OPG, the less clast activation.
increased bone turnover with high RANK-L and low OPG by blasts

of RANK receptors on clasts also affects turnover ratio - more receptors, more bone resorption (as in hypoestrogenism)

Question 15

Why are ALP levels increased in Paget’s?

Answer 15

alkaline phosphatase levels increase during active bone formation
ALP is a byproduct of osteoblast activity!

Question 16

Describe osteoclasts - how would you identify them on biopsy?

Answer 16

Multinucleated (normal: 2-5 nuclei)
Foamy cytoplasm
Ruffled border at contact with bone
+ for tartrate-resistant alkaline phosphatase (TRAP-positive)

In Paget’s: larger and more nucleated (up to 100)

Question 17

Describe the extrinsic pathway of apoptosis. What is the consequence of mutations of the Fas receptor or Fas ligand?

Answer 17

FasL binding of Fas receptors allows for trimerization of Fas receptors.
Cytoplasmic “death domains” of Fas receptors form a binding site for Fas-associated death domain (FADD) adapter protein, which stimulates the activation of initiator caspases.

Fas-FasL interaction necessary for negative selection in thymic medulla.
Mutations of FasL or Fas receptor can prevent apoptosis of autoreactive lymphocytes, increasing risk of autoimmune disease (basis of autoimmune disorders!).

Question 18

What is the normal mechanism of vaccine protection against bacteria? What is the mechanism for C. tetani?

Answer 18

Most bacteria: Circulating antibodies bind to microbial cells to signal both macrophage phagocytosis and complement fixation to cause bacterial death.

Tetanus: Humoral immunity specific for the tetanus toxin (tetanospasmin protein toxin that can travel via retrograde axonal transport into the CNS)
Neutralization of the toxin with antitoxin antibodies

Question 19

Mechanism of C. tetani exotoxin tetanospasmin?

Answer 19

travels retrograde to the CNS

blocks release of inhibitory neurotransmitters from inhibitory motor interneurons in the CNS (loss of inhibition = sustained contraction)

Question 20

1yo male with recurrent, indolent skin infections and gingivitis, plus delayed separation of umbilical cord after birth? Inheritance?

Answer 20

LAF-1 integrin (CD18) defect
Leukocyte Adhesion Deficiency (type 1)

Autosomal recessive

Skin infections would be WITHOUT pus formation

Question 21

What type of hypersensitivity disorder is myasthenia gravis? Hypersensitivity pneumonitis? Contact dermatitis?

Answer 21

MG = Type II

HP = Type III or Type IV

CD = Type IV

Question 22

What is Goodpasture syndrome?

Answer 22

autoantibodies formed against noncollagenous domain of alpha-3 chain of collagen IV (anti-glomerular basement membrane/anti-GM antibodies)
Type II hypersensitivity

cause inflammatory destruction of BM in renal glomeruli and lung alveoli

Question 23

Pt with sacral agenesis with lower extremity paralysis – risk factor?

Answer 23

Caudal regression syndrome

Associated with poorly controlled maternal diabetes

Question 24

Pt stung by bee with edeamtous and erythematous plaque with evanescent borders and mild central pallor - what hypersensitivity type? What Ig type characteristic? What released?

Answer 24

Type I
IgE crosslinked by antigen in allergic response (also anaphylaxis)
Degranulation of mast cells and basophils - release histamine and heparain, forms the wheal described above

Question 25

Which cytokine responsible for class switching of B cells?

Answer 25

IL-4
produced by Th2 cells
facilitates growth of B cells and Th2 differentiation
also antibody isotype switching to IgE and IgG

Question 26

Male pt with 2mo. lower back pain and morning stiffness - limited anterior flexion of spine and inflammation/early fusion of sacroiliac joint?

Answer 26

Ankylosing spondylitis

Question 27

What are the seronegative spondyloarthropathies? Genetic association?

Answer 27

Psoriatic arthritis
Ankylosing spondylitis
Inflammatory bowel disease
Reactive arthritis

Strong association with HLA-B27 (codes for HLA MHC class I)

Question 28

What is the most specific serum autoantibody for rheumatoid arthritis?

Answer 28

anti-cyclic citrullinated peptide antibody
HIGH SPECIFICITY
(more specific than anti-IgG antibody)

Question 29

2yo pt with urine sample turned black - deficiency? Inheritance?

Answer 29

Alkaptonuira / ochronosis
Congenital deficiency of homogentisate oxidase in degradation pathway of tyrosine to fumarate

Autosomal recessive, benign but arthralgias may occur (homogentistic acid toxic to cartilage)

Question 30

Pt with X-linked mutation of 5’-phophoribosyl-1’-pyrophosphate (PRPP) synthetase gene that increases Vmax of enzyme?

Answer 30

Gout

increased purine production = increased turnover of purines = hyperuricemia (increased production)

Question 31

Primary cell type responsible for the intense inflammatory response in pts with gout? Treatment targeting these cells?

Answer 31

Neutrophils (due to phagocytosis of monosodium urate crystals)

Colchicine inhibits MT polymerization
inhibits neutrophil chemotaxis

Question 32

38yo pt with pain and stiffness in shoulders and knees - brown spots on sclerae and diffuse darkening of helix of ears? Enzyme deficiency?

Answer 32

Homogentistic acid oxidase

Alkaptonuria (autosomal recessive)
accumulated homogentistic acid causes pigment deposits in connective tissue throughout body - causes ankylosis and motion restriction

Question 33

Pt with gum bleeding, petechiae, corkscrew hair, on tea and toast diet? What is impaired?

Answer 33

Scurvy - vitamin C deficiency

hydroxylation of proline and lysine in the rough ER for collagen synthesis impaired.

Question 34

Pt with hyperextensible skin, tendency to bleed/bruise, and hypermobile joints? Disease/inheritance? Deficiency?

Answer 34

Ehlers-Danlos syndrome
heritable connective tissue disease, autosomal dominant

associated with abnormal collagen formation (multiple mutations/types)