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Block 6: Microbio, ID, Derm, Heme-Onc > Autoimmunity, Review (Week 9) > Flashcards

Autoimmunity, Review (Week 9) Flashcards

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Dermatology Board Prep flashcards
1
Q

Autoimmune disease

A

Refers to when adaptive immune system attacks self

Rheumatoid arthritis is most common (1%)

Lupus is another but less common (0.1%)

Women get autoimmune disease more than men

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2
Q

Autoinflammatory disease

A

When innate immune system responds to self

Examples: gout, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), Muckel Wells

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3
Q

Gout

A

MSU crystals directly stimulate immune response (inflammasome cleaves IL-1B to active form, activate NFkB)

Therapies: colchicine (inhibits MT formation and chemotaxis), corticosteroids, NSAIDs/COX/ASA, Anti IL-1 therapies

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4
Q

How do corticosteroids work

A

Lots of different ways to suppress immune system!

1) Prevent margination of leukocytes by getting rid of “sticky” adhesion molecules (ICAMs on endothelial cells and LFA-1 on leukocytes)
2) Decrease cytokines
3) Decrease NO
4) Decrease prostaglandins and leukotrienes
5) Induce apoptosis in lymphocytes and eosinophils

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5
Q

Side effects of corticosteroids

A

Short term: infection, hyperglycemia, increased BP, fluid retention, insomnia, irritability, euphoria

Long term: atherosclerosis, osteopenia/osteoporosis, cataracts, glaucoma, skin manifestations, Cushingoid, acne, myopathy

Idiosyncratic: osteonecrosis, pancreatitis, irregular menses/amenorrhea

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6
Q

Steps to autoimmunity

A

Genetic predisposition then environmental hit leads to abnormal immune response

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7
Q

After APC presents self-antigen to naive T cell, what can happen?

A

Note: this all happens in utero (9 month school for body to learn what is self)

1) Strong binding –> clonal deletion (good!)
2) Weak binding and no 2nd signal –> escape into circulation (could be bad later)
3) Binding and 2nd signal –> clonal expansion of T cell and auto-immunity (bad bad bad!)
4) Binding but no 2nd signal –> anergy (good!)

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8
Q

What is the 2nd signal for APC interaction with T cell and when does this happen

A

2nd signal is B7 (CD80/86) on APC with CD28 on T cells
–> this stimulates expansion and differentiation of naive T cells

Only get 2nd signal when inflammation present (cytokines lead to expression of…B7? CD28?)

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9
Q

Abatacept

A

CTLA4 immunoglobulin

Binds CD80/86 to block the second signal

This turns off upregulated T cells

Used in RA

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10
Q

TNF-alpha receptor

A

Many cells have TNF-alpha receptor

CIrculating TNF-alpha receptors soak up extra TNF-alpha to keep things in balance

Anti-TNF therapy by giving soluble TNF receptors to soak up extra TNF (etanercept)

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11
Q

Anti-TNF therapies

A

Soluble TNF receptor to soak up extra TNF and decrease inflammatory response

Etanercept: soluble TNF receptor

Infliximab: TNF receptor put on Fc fragment of antibody to give it longer half-life (chimeric antibody)

Golimumab and Adalimumab: NF receptor put on Fc fragment of antibody to give it longer half-life (human antibody)

Certolizumab: pegylated TNF (mab fragment)

Note: all need to be injected because if took orally, it would break down; also check for latent TB before giving because these drugs will open up granulomas and release TB!

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12
Q

Anti-IL1 therapy

A

Expensive, not as good as TNF therapy

Daily injections

Also don’t combine with TNF therapy (never combine biologics) because get more infections

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13
Q

B cell therapies

A

Rituximab (anti CD20 on pre-B cells) and epratuzumab cause B cell depletion (used for non-Hodgkin lymphoma)

Belimumab blocks B cell stimulation

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14
Q

Belimumab

A

Anti-BLyS antibody that inhibits soluble BLyS by binding to it in the serum –> allows more B cells to undergo normal process of apoptosis so not too many autoreactive B cells

BLyS is regulator in B cell survival and proliferation (prevents apoptosis)

Used for SLE (ANA positive in particular)

Expensive, and monthly injection, so usually not used unless other therapies not working

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15
Q

Anti-IL6 therapy

A

Tocilizumab used to block IL6 signaling

Used for RA

Once monthly infusion

Not used much (second line) because of hepatotoxicity (transaminitis?), hyperlipidemia, infection

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16
Q

Ustekinumab

A

Inhibits IL12, IL23 which normally drive Th differentiation to TH1, TH17

Used for psoriasis

Weaker response for psoriatic arthritis

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17
Q

Disease modifying anti-rheumatic drugs (DMARDs)

A

Alter course of disease, don’t just treat symptoms like some druge (motrin)

Historical: gold, penicillamine

Ex: Tofacitinib, hydroxychloroquine, glucocorticoids, sulfasalzine, methotrexate, leflunomide, cyclosporin, cyclophosphamide

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18
Q

Hydroxychloroquine

A

Used for RA, SLE, spondyloarthropathy

Stabilizes lipid membranes

Side effects: nausea, retinal toxicity, tinnitus

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19
Q

Sulfasalazine

A

Sulfa combined with aspirin

Unknown mechanism of action

Can cause G6PD deficient anemia, decreased WBC

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20
Q

Methotrexate

A

Folic acid analogue (remember antineoplastic by inhibiting purine synthesis)

Also reduces inflammatory cytokines (IL1, IL6), increases anti-inflammatory cytokines (IL10, IL2, gamma INF), decreases immunoglobulin production, inhibits COX2 and leukotrienes

21
Q

Leflunomide

A

Pyramidine analog (blocks de novo pathway)

Used for RA

Side effects: hepatic (worse than MTX)

22
Q

Azathioprine

A

Purine analog turned into 6-mercaptopurine (MP)

Used for SLE, RA, myositis

Side effects: infection, marrow suppression, allergic hepatitis, lymphoma, allopurinol inhibits its metabolism (reduce dose)

23
Q

Mycophoneolate mofetil

A

Used for SLE

T cell preferential (activated lymphocytes)

Inhibits T/B cell proliferation and Ab synthesis

Interferes with adhesion molecules

Inhibits induction of iNOS

Pregnancy category D (don’t give to pregnant women)

Side effects: nausea, diarrhea, marrow suppression

24
Q

Cyclophosphamide

A

Alkylating agent that closs links DNA

Used for SLE, vasculitis, refractory autoimmune disease

Side effects: opportunistic infection, lymphoma, leukemia, bladder toxicity, oral cancer, sterility, nausea

25
Q

JAK inhibitors

A

Tofacitinib

Blocks JAK so ILs can’t signal (IFN-alpha, IL-12, IL-23, IL-6)

26
Q

Criteria for Lupus

A

Need 4 for a diagnosis of Lupus

I’M DAMN SHARP

Immunobglobulins (dsDNA, Smith, antiphospholipid)

Malar rash

Discoid rash

ANA (antinuclear antibody)

Mucositis (oropharyngeal ulcers)

Neurologic disorder

Serositis (pleuritis, pericarditis)

Hematologic disorders (LOW blood cells)

Arthritis

Renal disorders

Photosensitivity

27
Q

Subsets of lupus associated with antibodies

A

Anti-dsDNA: glomerulonephritis

Anti-phospholipid: thrombosis, fetal loss

Anti-Ro/SS-A: rash, neonatal SLE

28
Q

ANA

A

99% of SLE subjects positive

Most sensitive for SLE

29
Q

Can you tell if someone is going to get lupus?

A

Yes, look at their autoantibodies 9 years before clinical presentation and see lupus antibodies!

30
Q

What do autoantibodies of lupus do?

A

Aren’t JUST a marker, they’re part of pathogenic process

Anti-DNA cause glomerulonephritis

Anti-Ro/La induce congenital heart block

Anti-platelet induce thrombocytopenia

31
Q

“Defective brakes and increased acceleration” in lupus

A

Defective brakes: persistence of reactive T and B cells, decreased T reg and suppressor T cells, decreased clearance of apoptotic cells, decreased clearance of immune complexes, decreased “anti-inflammatory” cytokines (TGF-B)

Increased acceleration: increased CpG DNA and DNA-ICs, which bind to TLR9 on DCs, abnormal TLR signaling (increased expression of TLR9 on B cells), increased production of activating cytokines (IFN-gamma, IL6), increased T cell activation, increased production of autoantibodies

32
Q

How do people with lupus deal with apoptotic cells?

A

People with lupus can’t clear apoptotic cells well

When apoptotic cells not cleared rapidly, they become necrotic and simulate an inflammatory response

Now because there is inflammation, there is going to be that 2nd signal so when DC presents self antigen to T cell, 2nd signal will allow for activation of T cell to self-antigen

33
Q

How might TLRs on dendritic cells and B cells contribute to SLE?

A

TLRs activate DCs to secrete IFN-alpha, and we see highly increased IFN-alpha in lupus

Increased IFN-alpha can increase IL10, BLyS/BAFF expression on B cells

34
Q

Environmental factors that activate SLE

A

UVB light (alter DNA structure, induce apoptosis in keratinocytes)

Females (estradiol prolongs life of autoreactive B and T cells, inactive X is rich in hypomethylated regions which can trigger TLR signaling, microchimerism?)

EBV (activates B cells, also EBNA 1 has homology to Ro so maybe body trying to make response against EBV but makes something that cross reacts with self (Ro)

35
Q

Where abnormalities in genes might be to contribute to SLE

A

C1q or MBL deficiency could impair clearance of apoptotic bodies

HLA-DR polymorphism could make it easier or more stimulatory when presenting peptides

IL10 polymorphism could increase B cell maturation

Fc Gamma receptor clears immune complexes

36
Q

Treatment for SLE

A

Exercise

UV light protection

Topical triamcinolole

NSAIDs

Low dose prednisone

Hydroxychloroquine (acts on TLR7, 9 to lower production of INF-alpha and TNF-alpha)

Anti-IFN-alpha antibody (MEDI-545) reduces skin rash

37
Q

Immune evasion strategies by pathogens

A

1) Antigenic variation
2) Latency
3) Interfere with immune functions

38
Q

Organisms that use antigenic variation

A

1) Borrelia burgdorferi, borrelia hermsii (surface lipoprotein)
2) Neisseria meningitidis, N. gonorrheae (pili)
3) Streptococcus (M protein)
4) Mycoplasma (variable adherence associated antigen)
5) Influenza HA protein (antigenic drift)
6) Plasmodium falciparum (erythrocyte membrane protein)

39
Q

Severe Combined Immune Deficiency (SCID)

A

Low B and T cell levels due to various mutations (IL-2Rgamma, ADA, RAG-1/2 recombination enzymes, genes that regulate MHC-II genes, JAK3)

Infants present in first few months of life with diarrhea and failure to thrive

Fatal infections with Candida albicans, Pneumocystis jiroveci, varicella, adenovirus, other viral infections

Can do genetic tests to diagnose SCID

Use TREC (T cell receptor excision circles) for current newborn screen for SCID

Treat with bone marrow transplant or enzyme replacement therapy (PEG-ADA)

40
Q

X linked agammaglobulinemia

A

No Bruton tyrosine kinase gene (Btk) gene so cannot make mature B cells

Affected boys have less than 100mg/dL of IgG, and no serum IgM or IgA; no B cells, but normal T cells

Btk also involved in B cell receptor signaling

41
Q

Hyper IgM syndrome

A

Usually X linked deficiency where helper T cells lack CD154 and cannot interact with B cells

B cells cannot switch from production of IgM to other IgG, IgA, or IgE

42
Q

Selective IgA deficiency

A

Most common inherited immunodeficiency

Patients are relatively healthy and asymptomatic

Allergies to dietary antigens

Atopy because patients unable to block absorption of environmental antigens from their GI surfaces

43
Q

Common variable immune deficiency (CVID)

A

Group of 150 immunodeficiencies

Features include hypogammaglobulinemia

Humoral immune deficiency onset after age 2

Common infections: S pneumoniae, H influenzae, Klebsiella, meningitis, diarrhea, systemic infections

May have abnormal T cell function and immune disregulation

44
Q

Symptoms of antibody deficiency

A

Children remain well for 6 to 9 months after birth because of maternal IgG

Infections include sinusitis, otitis media, pneumonias, irreversible bronchiectasis

S pneumoniae, H influenaze, N meningitidis, Salmonella, Shigella, Campylobacter, Giardia, rotavirus too

Chronic meningitis with enterovirus can be fatal

Rheumatologic symptoms (septic arthritis) in 10-30%

Vaccination with inactivated agents is futile

Live vaccines should be avoided (vaccine-induced poliomyelitis has occurred)

45
Q

Splenectomy and susceptibility to encapsulated bacteria

A

Spleen clears blood of bacteria and produces antibodies

Liver effective at removing opsonized bacteria and spleen more efficient in removing nonopsonized bacteria

“Overwhelming pneumococcal sepsis syndrome” occurs in splenectomized children and can also occur in adults (mortality 40-80%)

Splenectomized patients at increased risk for S pneumoniae, H influenzae, N meningitidis

Malaria and babesiosis more severe post-splenectomy

Functional asplenia in Hodgkins disease, immune thrombocytopenia, sickle cell disease

Pneumococcal vaccine given at least 2 weeks before elective splenectomy

46
Q

Complement deficiency and susceptibility to disease

A

Classical pathway: increased collagen vascular disease (impaired clearance of immune complexes), H influenzae, S pneumoniae

Alternate pathway: increased N meningitidis

Junction of pathways (C3): increased H influenzae, S pneumoniae

Membrane attack complex: increased N meningitidis

Mannose binding lectin: decreased TB, increased HIV progression, increased S aureus, S pyogenes

47
Q

Chronic granulomatous disease (CGD)

A

Defective NADPH oxidase

Phagocytes cannot produce O2 impaired killing of phagocytosed bacteria

Get chronic bacterial and fungal infections, granulomas, abscesses in lungs, liver, brain, bone; soft tissue infection

Susceptible to catalase + organisms

Nitroblue tetraxolium (NBT) test is negative in CGD (doesn’t turn blue)

Treat with TMP-SMX or INF-gamma to prevent bacterial infections; allogenic stem cell transplantation

48
Q

Diabetes and susceptibility to infection

A

Hyperglycemia impairs leukocyte function (adherence, chemotaxis, phagocytosis, oxidative burst)

Increased susceptibility to respiratory tract infections (should get influenza and pneumococcal vaccines)

UTI

Limb-threatening infections of foot (loss of sensation and blood supply)

Pseudomonas otitis externa, rhinocerebral mucormycosis only in diabetics

49
Q

Bacterial infections associated with fever and neutropenia

A

Due to indwelling IV catheters, get bacteremia; mostly gram positive now

Gram positive: S epidermidis, S aureus, streptococci, enterococci

Gram negative: Pseudomonas, E coli, Klebsiella

Block 6: Microbio, ID, Derm, Heme-Onc (10 decks)

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