Immunology and Miscellaneous Questions

Question 1

t** List 3 rheum conditions where the above pathway can cause disease (2020)**

Answer 1

Gout
-Autoinflammatory
-AOSD
-
-Others: SLE, CPPD, RA, Sjogrens, Ank spond, SSc

Question 2

Which AB assoc’d w/ which ANA IF patterns (2020)
-Peripheral (rim)
-Homogeneous (diffuse)
-Speckled
-Cytoplasmic
-Nucleolar

Answer 2

Peripheral (rim) = dsDNA
–Acutely ill SLE
-
-Homogeneous (diffuse) = DNA-histone, Mi2
–SLE, discoid, RA, elderly
-
-Speckled = Ro, La, Smith, U1-RNP, Ku
–SLE, MCTD, Discoid, RA, SSc, elderly
-
-Cytoplasmic = Jo1, mitochondrial, smooth muscle
-
-Nucleolar = Topoisomerase, RNAP3, TH/TO, PM-SCl, U3-RNP
– SSc, SLE, RA, SS

Question 3

** Describe complement C3 and 4 in: HSP, acute cholesterol emboli, RA, RA vasculitis, cryoglobulinemia, lupus with GN, PAN, factor H deficiency (2014)**

Answer 3

HSP: transiently low, but then normal
-SLE and APS: both low
-Acute cholesterol emboli: transient low then normal
-RA: normal
-RA vasculitis, both low, but more C3 low
-Cryo: Low c4 more than low C3
-PAN: normal; low if HBV PAN
-AAV: normal
-IE: C3 lower more than C4
-Factor H deficiency: Low C3 only
-PSGN: Low C3 more than C4
-MPGN: Low C4 more than C3

Question 4

Complement activation pathway

Answer 4

1st to act: Alternative pathway = PAMP/DAMP activates complement cascade
-2nd: Lectin = mannose binding lectin binds pathogen
-3rd: Classical = CRP or AB binds Ag on pathogen
-
-All pathways cause C3 cleavage to C3a and C3b
-C3b binds to pathogen surface
-All recruit inflamm cells (C3a), opsonize pathogen (C3b), and cause cell membrane perforation
-
-C3 convertase forms C5 convertase to cleave C5 to C5b and anaphylatoxin C5a
-Together w/ C6, 7, 8, 9 = forms membrane attack complex

Question 5

** Immunology: 5 components of innate immune system. **

Answer 5

Skin barrier
-Complements
-Phagocytes (neutrophils, macrophages, dendritic cells)
-Sensors (PAMPs and DAMPs)
-PRRs (pattern recognition receptors) such as TLRs
-Effector cytokines

Question 6

Describe 2 steps to activate IL1 and IL18

Answer 6

TLR activation → NFKb → proIL1
-PAMPs/DAMPs activate NLRP3 inflammasome to cleave procaspase 1 → caspase to cleave IL1

Question 7

3 roles of neutrophils

Answer 7

Phagocytose,
-Degranulate,
-NETosis

Question 8

3 roles of macrophage

Answer 8

Phagocytose pathogens
-Activate T cells
-M1 release proinflammatory cytokines (eg TNF, IL1, IL6, IL 23)
-M2 release antiinflammatory cytokines (eg IL10, TGFb)

Question 9

Role of NK cells

Answer 9

NK cells (activated by T1 IFN, IL12, 15, 18 produced by macrophages and DCs)
–Destroy virally infected cells or tumor cells
–secrete cytokines: IFNg, TNFa
–Activate (and can destroy) macrophages, DCs, T cells

Question 10

Role of Dendritic cells

Answer 10

Conventional DCs - ingest, process, and present Ag to T cells

-Plasmacytoid DC’s - produce Type 1 IFN in viral infxns
–Can produce: T1 IFN, IL12, 15, 18

Question 11

Examples of APCs

Answer 11

Nonprofessional (all nucleated cells) = MHC1 (intracellular bacteria/virus/tumor) for CD8 cytotox cells that kill cancer/infected cells via cytotoxic granules or Fas mediated apoptosis

-Professional (DCs, macrophages, B cells) = MHC2 (extracellular antigen) for CD4 T helper cells to polarize immune response

Question 12

3 roles and types of B cells

Answer 12

Differentiate and produce ABs
-Act as APCs
-Produce cytokines
-
-Types (determined in Spleen)
-B regulatory (stop inflamm and expand Treg)
-Marginal zone B cells (1st line of defense against blood borne pathogens)
-Follicular - differentiate into plasma or memory B

Question 13

Role of AB’s

Answer 13

Neutralize,
-Opsonize
-Activate classical complement pathway
-ADCC (AB dependent cell mediated cytotox) via NK cells, PMNs, Eos, Macrophages

Question 14

Role of BAFF

Answer 14

Proteins secreted by myeloid and activated T cells to prolong B cell survival and promote B cell differentiation / maturation
–Increased levels in SLE
-

Question 15

What are roles of Type 1 vs Type 2 vs Type 3 IFN

Answer 15

Type 1 - IFN a/b - activate innate immune response like NK cell function to induce antiviral response

-Type 2 - IFNg - activates macrophages to phagocytose and secrete inflamm cytokines

-Type 3 - Structurally related to IL10 cytokines
–Similar to IFNb for viral infxn

Question 16

** Immunology: The most important component of adaptive immune system. **

Answer 16

T cells
-B cells
-APCs

Question 17

** Immunology: How do naïve T cells get activated. **

Answer 17

Signal 1: APC MHC complex with TCR on T cell
– MHC 1 (on all nucleated cells) with CD8
– MHC 2 (on professional APC) with CD4

-Signal 2 – CD 80/86 on APC with CD-28 (CD40-40L) on T cell
– Costimulation molecules
– CTLA4 agonist abatacept binds to CD28 on T cells, prevents interaction with CD80/86 on APCs

-Signal 3 - cytokines

Question 18

** What are the functions of Th1, Th2, Th17, T reg and what are they activated by and what do they produce **

Answer 18

TH1 – *Activated by IL-12. Produces IFN-gamma and TNF-alpha** for cell mediated response via macrophages and CD8+ cytotox T cells against Intracellular pathogens.
–Also suppress Th2 differentiation (vice versa)
-
-TH2 – Activated by IL 4. Produces IL4, IL5, IL13 for humoral response via B cells and AB production against extracellular pathogens & parasites
–Also support fcn of Eos, mast cells, M2 macrophages
-
-TH17 - Activated by IL6, TGF-B. Produces IL-17, 22 for immune response against extracellular pathogens/fungi at mucosal surfaces resistant to Th1/2
-
-Treg for immune tolerance
-Produces TGFb, IL10 to block effector T cells
-Cytolysis to cause apoptosis of T cell
-Metabolic disruption by preventing cytokine activation of T cell
-Inhibiting DC maturation/function
-
-Tfh cells (T follicular cells) - in peripheral lymph tissues
– Induced by IL6 and produce IL4 to activate naive B cells with CD40 costimulatory signal
-
-**SEE CHART

Question 19

4 types of hypersensitivity

Answer 19

THINK ABCD
-Type 1: Allergic Anaphylaxis Atopy
– IgE response for mast cell degranulation
-
-Type 2: AntiBody
-
-Type 3: immune Complex
-
-Type 4: Delayed type = NOT AB mediated; instead, Th1 (macrophage activating), Th2 (eosinophils), CD8 T cells (direct cytotox), or T cells (neutrophil activation)

Question 20

** Immunology: Name costimulation molecules and why are they important. **

Answer 20

Ligand on APC (Molecole on T cell)

-CD 80/86 (CTLA4= inhib T cell activation or CD28 = activates T cell activation)

-PDL1/PDL2 (PD1)

Question 21

** List 5 major acute phase proteins produced in the liver.**

Answer 21

IL-6 stimulated generation of acute phase proteins by the liver
– CRP
– Fibrinogen,
– Ferritin
– Haptoglobin
– Ceruloplasmin
– Hepcidin
– Alpha-1-antitrypsin,
– Serum amyloid A
– Alpha-2-macroglobulin,

Question 22

** Which cytokine is involved in promoting the acute phase response?**

Answer 22

IL6

Question 23

** iNOS:
-Name cytokines that increase iNOS
-Name effects of nitric oxide on the joint**

Answer 23

IL12, IL17, TNFa, IL6, IFNg

-Nitric oxide plays a role in vascular function and immune regulation. Correlated w/ levels of proinflammatory cytokines, cellular injury, and cartilage destruction

Question 24

** Superantigens:
-List differences of superantigens compared to conventional peptide antigens
-Name one example of a superantigen and associated disease**

Answer 24

Superantigens are foreign antigens (eg S Aureus, strep pyogenes, viral) that can bind Vbeta chain of TCR and directly bridge T cell R w/ any MHC2 molecule outside Ag binding groove to cause nonspecific T cell activation. They do not need to be processed by APC

-Activates T cells to release cytokine storm (eg S Aureus causing toxic shock syndrome, food poisoning w/ enterotoxin A

-Activates b cells without need for T cell help

Question 25

** What is immunologic tolerance**

Answer 25

Tolerance = when immune system encounters Ag that it is programmed not to respond to or eradicate

OR

-a state where the immune system is purposefully unresponsive to antigens that it is typically capable of responding to.

Question 26

** 2 mechanisms to develop immune tolerance **

Answer 26

Central tolerance (during initial development at thymus for T cells and bone marrow for B cells)
– Thymic selection of T cells - self Ag presented by MPC to T cells in thymus. T cells reacting too strongly are deleted via negative selection.
-
– Bone marrow selection of B cells - B cells interacting too strongly w/ self Ag in bone marrow selected for inactivation (anergy), apoptosis or receptors editing (rearranged to not recognize self antigen)
-
-Peripheral tolerance (selection that happens after T/B cells leave organ of origin)
– Clonal anergy - self reactive T cells ir B cells encountering self-Ag without 2nd costimulatory signals results in unresponsive anergy or apoptosis
-
– Immune checkpoints - self reactive T cells bind APC with CTLA4 to cause cell cycle arrest
-
– Treg and Breg - secrete IL10, TGFb to induce Treg (does more of the same), suppress Th1/17/18, or suppress macrophages, NK, neutrophils, and cause T cell apoptosis
-
– Idiotype network theory - ABs directed against self reactive antibodies
-

Question 27

** Name 2 anti-inflammatory cytokines**

-** Name 2 anti-fibrotic cytokines **

Answer 27

IL10, TGFB
IL4, 6, 11, 13

-Antifibrotic: IL10, IL12, IFNg

Question 28

** List 2 major components of nucleosomes
-How are nucleosomes linked to each other
-How are nucleosomes generate during apoptosis **

Answer 28

Nucleosomes are made of histones and DNA
-They are linked by LINKER DNA
-They are made during apoptosis when endonucleases cleave chromatin

Question 29

** Draw and describe a rheumatoid factor**

Answer 29

RF is an antibody that binds Fc portion of IgG
-It can also exist as IgM

Question 30

** IL-17: Discussed its natural use and list 2 cytokines related to its release**

Answer 30

IL17 for defense against extracellular fungal and bacterial infection

-2 cytokines related to its release: IL1, 6,

Question 31

** Discuss TLRs**

Answer 31

TLRs are pattern recognition receptors (PRRs) that mediated responses to PAMPs/DAMPs

-Signaling through TLR activates transcription factors (eg NFKb, IFN) to produce proinflammatory cytokines (IL1, 6, TNF)

Question 32

** Give two names of B-Cell receptors and discuss their functions (BAFF/BLyS).

Answer 32

BAFF-R -B cell activating factor
–Promotes immature B cell survival and maturation

-Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)
–B cell regulation
–Class switch recombination

-BCMA

Question 33

Discuss the inflammasome

Answer 33

Intracellular cytoplasmic protein complex of the INNATE immune system

-NLRP3 inflammasome created when NLRP3 (intracellular sensor for PAMP/DAMP) interacts w/ adaptor proteins ASC and Cardinal

-Activates caspase 1 to cleave proIL1b to active form to cause inflammation to fight infection (dysfunctional in AOSD, autoinflamm, gout)

Question 34

Adhesion molecules in the neutrophils:
-What are they?
-Name 3 adhesion molecules and their ligands involved in mediating endothelial and leukocyte interaction

Answer 34

Adhesion molecules allow neutrophils to stick to vascular endothelium and move into tissues, or to each other

-Selectins → bind to a specific sialylated glycoprotein
-Integrins → bind intercellular adhesion molecules (ICAM)
-Platelet-endothelial cell adhesion molecules (PECAM) → binds to other PECAMs

Question 35

** Innate immune system:
-List 3 cell types and 3 molecules involved in the innate immune system **

Answer 35

3 cell types:
-Dendritic Cells
-Neutrophils, Eosinophils
-Macrophages
-NK Cells
-Platelets
-
-3 molecules:
-Histamine
-Bradykinin
-Prostaglandins
-C5a
-C3a
-Chemokines
-Cytokines: IL-1, IL-8, TNF

Question 36

** List 4 disease association with anti-Ro and the frequency of positivity in each disease. **

Answer 36

Sjogrens 75%
-SLE 40%
-MCTD rare
-Diffuse SSc 10-20%
-RA 5%

Question 37

** List the disease association with anti-Jo and the frequency

Answer 37

Antisynthetase 20-30%

Question 38

** List the disease association with anti-histone antibodies and the frequency. **

Answer 38

Drug induced lupus

-Frequency depends on the drug:
–TNFa = 60%,
–Minocycline 20%

Question 39

** What does ENA measure: What are the known antibodies in an ENA panel**

Answer 39

Ro, La, Sm, RNP, Jo1, Scl70

-**NO ANTICENTROMERE

Question 40

** What are anti-citrulline antibodies and what is the role of ACPAs?**

Answer 40

Autoantibodies against citrulline residues on proteins formed by deimination of Arg by peptidylarginine deiminase

-ACPA roles
–Stimulate innate immune cells by inducing IFN to polarize macrophages to proinflammatory M1 subset → TNFa and Th1/17
–Activate complement via CLASSICAL and ALTERNATIVE (not lectin)
–Bind and stimulate OC to produce IL8

Question 41

** How does ACPA cause erosions - write out mechanism.**

Answer 41

• ACPA forms immune complexes with citrullinated proteins that deposit in the synovium → local inflammation, inflammatory cytokines: TNF-α and IL-1 that stimulate OC differentiation and activation → bone resorption and erosions.

Question 42

**There are proinflammatory cytokines. How do they affect OC (2 MOA) and OB (2 MOA) to cause erosions? **

Answer 42

OC:
– TNFa, IL6, IL17 promote OC differentiation

-OB:
– Low conc TNF stimulate OB differentiation (high conc inhib OB fcn/bone formation)
– IL3 increases RANKL expression to cause more OC differentiation

Question 43

Anti-citrulline peptides in synovium in RA

Answer 43

Fibrinogen
-Type 2 collagen
-Vimentin
-alpha-enolase

Question 44

** Cryo type, monoclonal association, and RF
-What is another type of protein found in cryoprecipitate **

Answer 44

1: MONOCLONAL against monoclonal; no
-2: MONOCLONAL against POLYclonal IgG; yes
-3: polyclonal against polyclonal IgG and IgM; yes
-
-Another protein: fibrinogen, factor 8, 13, vwf

Question 45

** What cytokines are most important in: RA, SLE, SSc, AS, PsA, OA, Gout, AoSD?**

Answer 45

RA = TNF, IL1, 6, RANKL
-SLE = IFN, BAFF,
-SSc = TNF, IL6, IL17
-AS = TNF, IL17, 23
-PsA = TNF, IL 17, 23
-OA = TNF, IL1, 6, 17
-Gout = TNF, IL1, 6
-AoSD = TNF, IL1, 6, 17, 18

Question 46

** List 4 potential inducers of nuclear kappa factor beta.
-List 4 gene families which are stimulated by nuclear factor kappa beta
-What inhibits it? **

Answer 46

Inducers: TNF, IL1, IL17, bacteria, virus, oxidative or physiologic stress

-Gene families stimulated by NFKB:
– COX2, MMP, Adhesion molecules, TNF, NOS

-Inhibitors: AntiTNF, Anti IL 1, GC, NSAIDs

Question 47

** List 6 cytokines that corticosteoirs suppress directly**

Answer 47

IL1, 2, 6, 17, TNFa, IFNg,

Question 48

** What is the Scl-70 antibody reacting with?
-What may it be associated with clinically **

Answer 48

Topoisomerase 1 (enzyme for winding/unwinding DNA during replication)

-Associated with Systemic Sclerosis

Question 49

** For 2 rheumatic diseases, outline the HLA allele associations and the mean by which these alleles lead to disease **

Answer 49

HLAB27 - molecular mimicry of immune system responding to foreign pathogen (eg viral) with similarities to HLAB27 causes autoimmunity. Homodimer can activate NK cells, or misfolding can cause protein stress response (IL23) autoimmunity

-HLADR4 Or HLA DRB1 in RA has shared isotope that allows presentation of citrullinated peptides to immune system and heightened immune response

Question 50

**IFNg:
-What 2 diseases is it implicated in the pathogenesis
-What new cell has been shown to express in
-What stimulates expression **

Answer 50

Diseases: autoinflammatory, MAS, Hashimoto’s thyroiditis

-Cells expressing IFNg:
– Th1 cells, CD8 cells, NK cells, APCs

-What stimulates its expression
– Activation of NK cells and T cells
– IL18
-

Question 51

** Future therapies: how would anti-CCP / anti-IL6 / nfkb / OPG work. **

Answer 51

AB against anti-CCP could prevent binding to citrinilated peptides and immune response

-IL6i (eg Toci) - blocking acute phase response, angiogenesis, hematopoiesis

-NFKb blocker - would block multiple cytokines (TNF, IL1, 6, 12) but may hv side effects on bone marrow suppression

-OPG - binds RANKL to prevent binding to RANK. ie similar to Denosumab to prevent OC activation and differentiation

Question 52

** Man with recurrent shoulder dislocation and FHX of sudden cardiac death List 10 findings on PE of his most likely underlying diagnosis**

Answer 52

Lens dislocation (ectopic lentils)
-Joint hypermobility
-Scoliosis
-Cardiac murmur (MVP - systolic click)
-Aortic dilatation (diastolic murmur)
-Myopia, drooping eyelid,
-Premature OA
-Skin hyperextensibility, scarring
-Spontaneous PTX
-Pectus excavatum/carinatum
-Arms longer than legs
-Long legs

Question 53

** Ganglion cyst
-List the 2 most common locations in the upper limb
-6 differentials for ganglion cyst.**

Answer 53

Wrist (dorsum)
-DIP
-
-Differential:
– RA nodule
– Gouty tophi
– Soft tissue tumor
– Epidermal cyst
– Synovial cyst
– Lipoma
– Giant cell tumor of tendon sheath
– Mucinous cyst
– Calcinosis
– Subcutaneous nodule
– Scar tissue

Question 54

** Mucinous cyst
-Most common location
-Most common underlying condition **

Answer 54

DIP extruding from synovium
-OA

Question 55

** Table with Odds Ratios: which factor is most associated and which is most protective
– what 2 things show statistical significance**

Answer 55

Most positive OR = associated
-Most negative = least associated
-
– Low p value and 95% CI

Question 56

Hazard ratio table.
-What is the % increased risk of a particular exposure

Answer 56

E.g. if HR is 1.15, then it is 15% increased, if HR is 0.9, then it is 10% decreased

Question 57

** Name 4 diseases associated with autoimmune inner ear disease (2020) **

Answer 57

Cogan, Behcet
-Susac, AAV, PAN
-SLE, RA, Sjogrens
-Ank spond, RPC
-APS
-Sarcoid

Question 58

DDX sensorineural hearing loss

Answer 58

Idiopathic Sudden SNHL (unilateral, NO vestibular symptoms, improves over 2 weeks regardless of treatment)

-Meniere’s (happens over years)

-Infectious (HSV, VZV, Lyme, VDRL, fungal, bacterial, abscess causing mass effect)

-Vascular (atherosclerosis, APS, vasculitis, hypercoagulability)

-Trauma (acoustic, barotrauma)

-Meds (aminoglycosides, HCQ, NSAIDs, loop diuretics)

-Cancer (mass effect - acoustic neuroma, mets, lymphoma)

-Neuro (MS, basilar migraine)

-Endocrine (DM, thyroid)

Question 59

sensorineural hearing loss workup

Answer 59

Imaging (MRI) to exclude retrocochlear mass

-CBC, inflammatory markers, infxn w/u (VDRL, hzv), APS AB, RF, AAV, ANA/ENA, hypercoag workup

-HSP70 (heat shock protein) - low sensitivity

-Serial audiograms

Question 60

** TEN rheumatic causes of recurrent polychondritis? **

Answer 60

Vasculitis
-RA
-SLE, Sjogrens
-Behcet
-ANk spond, ReA, PsA
-SSc
-PMR
-Retroperitoneal fibrosis

Question 61

FOUR complications of untreated recurrent polychondritis?

Answer 61

Auricular chondritis, Cauliflower ear
-Hearing loss (CHL or SNHL), tinnitus
Vestibular dysfunction

-Ocular = anything (cataracts, optic neuritis, corneal ulceration, EOM palsies, retinal vasculitis…)

-Saddle nose deformity, stuffiness, crusting
-Nasal chondritis

-Laryngo-tracheal stenosis

-Aortic/mitral regurg
-Aneurysm
Pericarditis, heart block, MI (coronary arteritis)

-Vasculitis, purpura, apthous ulcers, nodules

Question 62

** Stats question. Had to calculate Sn and Sp, PPV, NPV. (2014)**

Answer 62

Sensitivity (SnOUT): TP/TP+FN
-Specificity (SpIN): TN/TN+FP
-
-PPV: TP/TP+FP
-NPV: TN/TN+FN
-
-RRR = treatment effect group 1 - treatment effect group 2/treatment effect group 1
-ARR = treatment effect group 1 - treatment effect group 2
-NNT = 1/ARR