Autoimmunity, Review (Week 9) Flashcards
Autoimmune disease
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
Autoinflammatory disease
When innate immune system responds to self
Examples: gout, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), Muckel Wells
Gout
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
How do corticosteroids work
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
Side effects of corticosteroids
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
Steps to autoimmunity
Genetic predisposition then environmental hit leads to abnormal immune response
After APC presents self-antigen to naive T cell, what can happen?
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!)
What is the 2nd signal for APC interaction with T cell and when does this happen
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?)
Abatacept
CTLA4 immunoglobulin
Binds CD80/86 to block the second signal
This turns off upregulated T cells
Used in RA
TNF-alpha receptor
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)
Anti-TNF therapies
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!
Anti-IL1 therapy
Expensive, not as good as TNF therapy
Daily injections
Also don’t combine with TNF therapy (never combine biologics) because get more infections
B cell therapies
Rituximab (anti CD20 on pre-B cells) and epratuzumab cause B cell depletion (used for non-Hodgkin lymphoma)
Belimumab blocks B cell stimulation
Belimumab
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
Anti-IL6 therapy
Tocilizumab used to block IL6 signaling
Used for RA
Once monthly infusion
Not used much (second line) because of hepatotoxicity (transaminitis?), hyperlipidemia, infection
Ustekinumab
Inhibits IL12, IL23 which normally drive Th differentiation to TH1, TH17
Used for psoriasis
Weaker response for psoriatic arthritis
Disease modifying anti-rheumatic drugs (DMARDs)
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
Hydroxychloroquine
Used for RA, SLE, spondyloarthropathy
Stabilizes lipid membranes
Side effects: nausea, retinal toxicity, tinnitus
Sulfasalazine
Sulfa combined with aspirin
Unknown mechanism of action
Can cause G6PD deficient anemia, decreased WBC
Methotrexate
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
Leflunomide
Pyramidine analog (blocks de novo pathway)
Used for RA
Side effects: hepatic (worse than MTX)
Azathioprine
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)
Mycophoneolate mofetil
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
Cyclophosphamide
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
JAK inhibitors
Tofacitinib
Blocks JAK so ILs can’t signal (IFN-alpha, IL-12, IL-23, IL-6)
Criteria for Lupus
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
Subsets of lupus associated with antibodies
Anti-dsDNA: glomerulonephritis
Anti-phospholipid: thrombosis, fetal loss
Anti-Ro/SS-A: rash, neonatal SLE
ANA
99% of SLE subjects positive
Most sensitive for SLE
Can you tell if someone is going to get lupus?
Yes, look at their autoantibodies 9 years before clinical presentation and see lupus antibodies!
What do autoantibodies of lupus do?
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
“Defective brakes and increased acceleration” in lupus
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
How do people with lupus deal with apoptotic cells?
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
How might TLRs on dendritic cells and B cells contribute to SLE?
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
Environmental factors that activate SLE
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)
Where abnormalities in genes might be to contribute to SLE
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
Treatment for SLE
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
Immune evasion strategies by pathogens
1) Antigenic variation
2) Latency
3) Interfere with immune functions
Organisms that use antigenic variation
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)
Severe Combined Immune Deficiency (SCID)
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)
X linked agammaglobulinemia
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
Hyper IgM syndrome
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
Selective IgA deficiency
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
Common variable immune deficiency (CVID)
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
Symptoms of antibody deficiency
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)
Splenectomy and susceptibility to encapsulated bacteria
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
Complement deficiency and susceptibility to disease
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
Chronic granulomatous disease (CGD)
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
Diabetes and susceptibility to infection
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
Bacterial infections associated with fever and neutropenia
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
