BLD434 Section 6 Flashcards
Type I hypersensitivity
- Immediate (2-30 min rxn time); Anaphylaxis
- IgE mediated, mast cell degranulation; releases mediators like histamine
- Involves mast cells, basophils, eosinophils, Th2
- Ex: asthma, hay fever, food allergy
Type II hypersensitivity
- Cell or surface bound Ab
- Cause cytotoxicity, ADCC, complement activation
- Rxn time = 5-8 hours
- Involves IgG, IgM, phagocytes
- Ex: hemolytic anemia, HDFN, Goodpasture’s Syndrome, Grave’s Disease
Type III hypersensitivity
- Immune complex mediated
- Involves complement activation
- Rxn time = 2-8 hours
- Involves IgG, phagocytes, mast cells
- Ex: Arthus reaction, Rheumatoid arthritis, Systemic Lupus Erythematosus, “serum sickness”
Type IV hypersensitivity
- Delayed (24-72 hr rxn time)
- Only cell-mediated hypersensitivity; no Ab
- Sensitized T cells, activated macrophages (redness, swelling)
- Involves Th1, Tc (CD8+), macrophages
- Ex: Contact dermatitis, Celiac disease, poison ivy
Total serum IgE testing: uses, advantages, disadvantages
- RIST (Radio-Immunosorbent Test)
- Measures the overall level of IgE ab in the blood to assess if a person has an allergic predisposition
- Pros: simple & safe
- Cons: Lacks specificity
Skin prick testing: uses, advantages, disadvantages
- Used for Type I hypersensitivity
- Pros: A positive test is clinically significant. Simple, easy, very sensitive & specific
- Cons: Danger of systemic rxn. Traumatic to patient. Test limited to individual allergens
Allergen specific testing for IgE: uses, advantages, disadvantages
- RAST (Radioallergosorbent Test)
- Pros: Can be used when patient is taking anti-histamine. Requires a single skin puncture (less traumatic). Increased sensitivity
- Cons: Lower specificity than skin testing. Only tells if IgE is present, not if it’s responsible for pt symptoms
What cells are responsible for autoimmune disease?
CD4+ T cells, CD8+ T cells, and B cells.
What two proteins are involved in T lymphocyte self-tolerance? What can happen when they are defective in humans?
AIRE (Autoimmune Regulatory Element) & FOXP3 (Forkhead box protein P3)
Defects, like deletion mutations, will lead to autoimmune disease.
Relative risk
The likelihood of those with a risk factor developing an associated disease compared to those without the risk factor (general population). But, just because one has the risk factor, doesn’t mean they will get the disease
Ex: HLA gene susceptibility
Relative risk score interpretation: 1, >1, and <1
1 = no association
>1 = positive association
<1 = negative association
Ex:
>150 means pt is 150x more likely than gen. pop. to develop the AI disease if they have the HLA associated allotype.
0.02 means pt only has 1/50 risk of developing the disease
How are HLA alleles involved in the development of autoimmunity?
HLA, MHC I, and MHC II present peptide Ag to CD4 and CD8 T cells. Then T cells lose tolerance to self-Ag (lose their ability to prevent an immune response to self-Ag). Then autoreactive T cells get activated, leading to an immune response against self-tissues.
6 Risk Factors for Autoimmune Disease Development
1) Defects in AIRE or FOXP3
2) Gender (females more often affected)
3) Environment:
Traumatic injury, Molecular mimicry, chemicals, pollutants
4) Polyclonal B cell activation
5) Inhibitory Fc gamma R polymorphisms
6) Genetic mutations in C1-C4
Molecular mimicry
An immune response to a pathogen triggers a TCR/BCR activation that cross-reacts with self-Ag
Epitope spreading
The development of an immune response to epitopes distinct from the disease-causing epitope. This gives the immune system the ability to attack multiple targets on a pathogen.
Is responsible for chronic worsening of autoimmune disease the longer the person has it.
Can be attributed to sloppy linked recognition between B and T cells.
IVIg
Intravenous immunoglobulin -
A treatment for patients who cannot make Ab due to an inherited immunodeficiency.
Currently used for Grave’s disease and immune thrombocytopenia.
RhoGAM
A medicine given to pregnant women/moms who are Rh-negative to prevent hemolytic disease of the newborn.
Polyclonal IgG is purified from pooled serum to get anti-Rh Ab. It contains Rh-positive proteins.
Monoclonal antibody preparation treatment
Recombinant protein therapies used to target and kill tumor cells or act as immunosuppressants
Monoclonal vs. Polyclonal (antiserum) Ab preparations
Monoclonal: Ab is all identical (same isotype and bind to same epitopes) and is produced by a clone cell (hybridoma)
Polyclonal: has multiple isotypes from different plasma cells that help have affinity to multiple epitopes.
3 Monoclonal Ab therapies used to treat RA
1) Anti-TNA-alpha
- blocks joint destruction
2) Anti-alpha 4 integrin
- blocks the homing of inflammatory cells, which prevents autoimmune tissue destruction
3) Anti-IL-1 or anti-IL-6
- interferes with macrophage inflammatory cytokines with anti-TNF-alpha
Which hypersensitivity responses can cause autoimmune disorders?
Type II, III, and IV
Type II is most common
What 4 autoimmune diseases have a much higher incidence rate in women than in men?
Hashimoto’s disease, Grave’s disease, Addison’s disease, SLE
Celiac Disease
- Gluten sensitivity
- Type IV hypersensitivity
- Associated with dermatitis herpetiformis due to high serum titier of IgA anti-TTG
Autoantibodies for diagnosis of Celiac disease
IgA anti-TTG
IgA anti-gliadin
IgA anti-endomysium
2 forms of Inflammatory Bowel Disease
1) Ulcerative Colitis
- Only inflames the large intestine
- Associated with ANCA (p & c)
2) Crohn’s Disease
- Can inflame any part of the intestinal tract
- Associated with skin lesions
ANCA
Anti-neutrophil cytoplasmic antibodies
Seen in Ulcerative colitis (an IBD) - usually in the peripheral pattern pANCA
cANCA
Cytoplasmic pattern of Anti-neutrphil cytoplasmic antibodies.
Seen in Wegener’s granulomatosis
Pernicious Anemia
Deficiency in cobalamin (vitamin B12) that causes a lack of healthy RBCs.
Autoantibodies:
- Anti-intrinsic factor
- Anti-parietal cell
Myasthenia gravis
- Autoimmune disorder where antibodies attack neuromuscular connections by blocking or destroying ACH receptor sites.
- Auto-Ag = ACH-R
- Type II hypersensitivity
- Diagnose via RIA (Radioimmunoassay) to detect auto-Ab & serologic tests.
Multiple Sclerosis (MS)
- An inflammatory autoimmune disease of myelin around nerves in the CNS.
- Auto-Ag: MBP (myelin basic protein) and MOG (myelin oligodendrocyte glycoprotein)
- Demyelination around axons
- Type IV and Type II hypersensitivity
2 most common rheumatologic diseases
Rheumatoid Arthristis (RA) & Systemic Lupus Erythematosus (SLE or Lupus)
Why are rheumatologic diseases difficult to diagnose?
Symptom & lab test result overlap, so no test is completely specific or sensitive for the disease. Not all pt have the expected auto-Abs
FANA (define & titer interpretation)
Fluorescent Antinuclear Antibody Testing
- Screening test used to detect ANA for diagnosing SLE
- Results include titer & pattern
- Titer:
≤1:80 = Normal
≥1:160 = Positive
The higher the titer, the more severe the disease.
- 70% of elderly have low positive titer; so positive titer alone does not diagnose SLE. Also in RA, scleroderma, and Sjorgren’s syndrome
5 staining patterns observed in FANA
- Homogenous
- even staining
- Speckled
- nucleus stains evenly, except for centrosomes
- Nucleolar
- large discrete staining of nucleoli only
- Peripheral
- outlines nucleus
- Mixed
ANA
Antinuclear antibodies
- General titer. Tested for in FANA for Lupus diagnosis
ENA test & list 2 examples that are diagnostic for Lupus
Extractable Nuclear Antigen test
Checks for Ab in the blood.
- Anti-dsDNA
- Anti-Sm (Ab to Smith Ag)
Lupus autoimmune mechanism hypersensitivity
Type III hypersensitivity
Caused by IgG autoantibodies to nuclear components (DNA, RNA, nucleoproteins) forming immune complexes with these auto-Ags and deposit in tissues, which activates complement, leading to inflammation.
Specific ENA associated with drug-induced Lupus
Anti-histone Ab
(only ENA positive in drug-induced Lupus)
Why can Lupus patients have false positive Syphilis test?
Lupus patients can develop the anti-cardiolipin Ab, and cardiolipin is the target in non-treponemal syphilis testing.
Rheumatoid Factor (RF)
A quick non-specific screening test for RA; IgM, IgG, and IgA to the Fc portion of IgG (anti-immunoglobulin Ab); attack healthy tissues/cells.
- Can also be found in syphilis, lupus, hepatitis, Tb, mno, and Sjogren’s syndrome.
How does the IgM isotype RF screening test differ from those for IgG and IgA RF isotypes?
Pt serum is added to RBC or latex particles coated with human IgG, and if particles agglutinate, the test is positive for RF.
Only IgM will cause agglutination because it is a pentamer.
IgG RF and IgA RF are tested by EIA and these isotypes are more disease specific and sensitive; present in 100% of RA patients.
Anti-CCP testing
Anti-cyclic Citrullinated Peptide
- Screening test paired with RF for RA diagnosis
Citrulline
A non-standard amino acid created by deamination of arginine by peptidylarginine deaminase. This process of is post-translational modification of joint proteins fillagrin, vimentin, and fibrin.
- Involved in Anti-CCP for RA diagnosis
Diagnostic criteria for RA
- Morning joint stiffness (over 1 hr)
- Soft tissue swelling (3+ joints)
- Swelling of fingers or wrists
- Symmetric arthritis
- Rheumatoid nodules
- RF present
- Joint erosions (x-ray)
Only need TOP FOUR criteria for 6 weeks.
Lab test to follow course of SLE & interpretation
Increase:
- ESR (erythrocyte sedimentation rate)
- CRP (C-reactive protein)
- Anti-dsDNA titer
- Urine protein (glomerulonephritis)
Decrease:
- CBC
- Complement (C3, C4, CH50)
- Serum albumin
Lab test to follow course of RA & interpretation
Increase:
- ESR
- CRP
Decrease:
- Complement components (C3 and C4)
