Autoimmunity, Review (Week 9)

Question 1

Autoimmune disease

Answer 1

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

Question 2

Autoinflammatory disease

Answer 2

When innate immune system responds to self

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

Question 3

Gout

Answer 3

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

Question 4

How do corticosteroids work

Answer 4

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

Question 5

Side effects of corticosteroids

Answer 5

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

Question 6

Steps to autoimmunity

Answer 6

Genetic predisposition then environmental hit leads to abnormal immune response

Question 7

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

Answer 7

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!)

Question 8

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

Answer 8

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?)

Question 9

Abatacept

Answer 9

CTLA4 immunoglobulin

Binds CD80/86 to block the second signal

This turns off upregulated T cells

Used in RA

Question 10

TNF-alpha receptor

Answer 10

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)

Question 11

Anti-TNF therapies

Answer 11

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!

Question 12

Anti-IL1 therapy

Answer 12

Expensive, not as good as TNF therapy

Daily injections

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

Question 13

B cell therapies

Answer 13

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

Belimumab blocks B cell stimulation

Question 14

Belimumab

Answer 14

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

Question 15

Anti-IL6 therapy

Answer 15

Tocilizumab used to block IL6 signaling

Used for RA

Once monthly infusion

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

Question 16

Ustekinumab

Answer 16

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

Used for psoriasis

Weaker response for psoriatic arthritis

Question 17

Disease modifying anti-rheumatic drugs (DMARDs)

Answer 17

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

Question 18

Hydroxychloroquine

Answer 18

Used for RA, SLE, spondyloarthropathy

Stabilizes lipid membranes

Side effects: nausea, retinal toxicity, tinnitus

Question 19

Sulfasalazine

Answer 19

Sulfa combined with aspirin

Unknown mechanism of action

Can cause G6PD deficient anemia, decreased WBC

Question 20

Methotrexate

Answer 20

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

Question 21

Leflunomide

Answer 21

Pyramidine analog (blocks de novo pathway)

Used for RA

Side effects: hepatic (worse than MTX)

Question 22

Azathioprine

Answer 22

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)

Question 23

Mycophoneolate mofetil

Answer 23

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

Question 24

Cyclophosphamide

Answer 24

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

Question 25

JAK inhibitors

Answer 25

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

Question 26

Criteria for Lupus

Answer 26

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

Question 27

Subsets of lupus associated with antibodies

Answer 27

Anti-**dsDNA**: **glomerulonephritis** Anti-**phospholipid**: **thrombosis**, **fetal loss** Anti-**Ro/SS-A**: **rash, neonatal SLE**

Question 28

ANA

Answer 28

99% of SLE subjects positive Most sensitive for SLE

Question 29

Can you tell if someone is going to get lupus?

Answer 29

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

Question 30

What do autoantibodies of lupus do?

Answer 30

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**

Question 31

"Defective brakes and increased acceleration" in lupus

Answer 31

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**

Question 32

How do people with lupus deal with apoptotic cells?

Answer 32

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

Question 33

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

Answer 33

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

Question 34

Environmental factors that activate SLE

Answer 34

**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)

Question 35

Where abnormalities in genes might be to contribute to SLE

Answer 35

**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

Question 36

Treatment for SLE

Answer 36

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

Question 37

Immune evasion strategies by pathogens

Answer 37

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

Question 38

Organisms that use antigenic variation

Answer 38

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)

Question 39

Severe Combined Immune Deficiency (SCID)

Answer 39

**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)

Question 40

X linked agammaglobulinemia

Answer 40

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

Question 41

Hyper IgM syndrome

Answer 41

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

Question 42

Selective IgA deficiency

Answer 42

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

Question 43

Common variable immune deficiency (CVID)

Answer 43

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

Question 44

Symptoms of antibody deficiency

Answer 44

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)

Question 45

Splenectomy and susceptibility to encapsulated bacteria

Answer 45

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

Question 46

Complement deficiency and susceptibility to disease

Answer 46

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

Question 47

Chronic granulomatous disease (CGD)

Answer 47

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

Question 48

Diabetes and susceptibility to infection

Answer 48

**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

Question 49

Bacterial infections associated with fever and neutropenia

Answer 49

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