Pathology of Immunity (Part I) Flashcards
What are some examples of Pattern Recognition Receptors? (3)
TLRs
NOD-like receptors and inflammasome
C-type lectin receptors
What are the 2 generative organs and what do they produce?
Bone marrow - lymphocyte stem cells and B cell maturation.
Thymus - maturation of T cells.
What are the 3 peripheral organs/tissues and what happens there?
Lymph nodes - lymphocytes can interact w/ APCs and Ags in circulating lymph.
Spleen - lymphocytes can interact w/ blood-borne Ags.
MALT - allows lymphocytes and plasma cells to be in the vicinity of Ags within the mouth and GI tract.
What is contained within the medulla of the thymus? (3)
Maturing T cells
Dendritic APC w/ lots of MHC I and II.
Hassall corpuscles (squamous cell nests)
What is the path that immature T cells take from the bone marrow to the place of maturation?
Bone marrow -> peripheral cortex of the thymus -> central medulla of the thymus
Where do T and B cells predominate in the peripheral lymphatic organs?
T cells - paracortex
B cells - germinal centers
What occurs in the peripheral lymphatic organs? (3)
T and B cell clonal expansion.
B cell differentiation.
Migration of T cells and plasma cells out of lymph nodes and into circulation.
MHC I are on:
What do they recognize?
Ags are processed by:
What cells do they present to?
All nucleated cells.
Intracellular Ags (viral, tumors, etc.).
Proteasome.
CD8+ cells (cytotoxic).
MHC II are on:
What do they recognize?
Ags are processed by:
What cells do they present to?
APCs.
Extracellular Ags.
Endolysosomal enzymes.
CD4+ cells (helper T cells).
Which chromosome code for HLA molecular structure?
Chr 6
What is the significance of the extensive heterogeneity of HLA haplotypes?
What is the clinical importance?
Differences in fighting off illnesses.
Differences in allergic sensitivities.
Transplanted organs.
Associated AI diseases.
MHC I evoke ______ of ______ pathogens.
MHC II evoke a response to ______ pathogens by ________.
Killing of intracellular pathogens.
Extracellular pathogens by CD4+ recruitment of Mo and T cells.
Humoral immunity can be T cell dependent or T cell independent. T cell independent responses can use: (2)
Isotype switching
Increasing affinity
IgM (2)
First Ig produced.
Pentamer - huge!
IgG (2)
Longest half-life.
Important in fetal protection.
IgA (2)
Mucosal defense.
Present in high levels in colostrum.
IgE (3)
Shortest half life.
Regulates hypersensitivity reactions.
High affinity binding to FC receptor on MCs, basophils, eosinophils.
NK cells destroy: (2)
Do they have TCRs or Ig?
What turns them off?
Stressed or abnormal cells.
No.
MHC I class expression turns them off.
What activates NK cells?
What inhibits NK cells?
+ Damaged cells recognized by NKG2D receptors.
- Self MHC molecules.
- Class I MHC (on all nucleated cells).
BCRs and TCRs are products of:
Multiple germline and randomized somatic genetic programming.
What happens if a large population of cells w/ the exact same genes is identified? (3)
Abnormal clone
Neoplasia
Lymphoma
What is the “backstory” of type 1 hypersensitivity (what you do NOT see)? (5)
- DCs present to naive T cell.
- T cells differentiate to Th2 cells.
- B cells undergo class-switching to IgE.
- Interleukins get involved
- IL-4: class switching, IL-5: eosinophil activation, IL-13: enhanced IgE production. - MCs get prepared by binding IgE to their FceRI receptor.
What DO you see in a type 1 hypersensitivity? (4)
MC activation:
- Degranulation: histamine release.
- Lipid mediators: LTB4, LTC4, LTD4, PG D2, PAF.
- Cytokines and chemokines: leukocyte recruitment (late phase).
Immediate vs. late reactions in type 1 hypersensitivity?
Immediate - MC mediators cause vasodilation, vascular leakage and SM spasm.
Late - inflammatory cells cause epithelial damage.
Eosinophilic esophagitis (3)
Food antigen-driven disease of childhood.
Recurrent dysphagia.
Weight loss - can’t swallow, hurts to swallow.
Type 2 hypersensitivity reactions can be due to: (2)
Autoantibodies
Exogenous antigens bound to cell surfaces.
What are the 3 mechanisms of type 2 hypersensitivity reactions?
Phagocytosis
Inflammation
Cellular dysfunction
Autoimmune hemolytic anemia
Target Ag:
Mechanism of disease:
Target Ag: RBC membrane proteins (Rh blood group Ags, I Ag).
Mechanism of disease: opsonization and phagocytosis of RBCs.
Autoimmune thrombocytopenia
Target Ag:
Mechanism of disease:
Target Ag: platelet membrane proteins (GpIIb: IIIa integrin).
Mechanism of disease: opsonization and phagocytosis of platelets.
What is unique about the basic mechanism of opsonization/phagocytosis in type 2 hypersensitivity reactions?
It does not require any cells (anemia, thrombocytopenia).
What is the mechanism of complement and Fc receptor-mediated inflammation in type 2 hypersensitivity reactions?
Damaged tissue allows for exposure of basement membrane.
What is Rheumatic Heart?
What sensitivity type?
AI dz of the heart.
Cross-reactive Abs that use molecular mimicry w/ streptococcal Ag and myocardial Ag.
Type 2.
What is the basic mechanism of antibody-mediated cellular dysfunction in type 2 reactions?
Dysfunction due to receptor blockage from disrupted endocrine or neural signaling.
Myastenia gravis
Target Ag:
Mechanism of disease:
Target Ag: Ach receptor.
Mechanism of disease: Ab inhibits binding of of ACh and down-regulated the receptors.
Type 2.
Graves disease
Target Ag:
Mechanism of disease:
Target Ag: TSH receptor.
Mechanism of disease: Ab-mediated stimulation of TSH receptors.
Type 2.
Insulin-resistant diabetes
Target Ag:
Mechanism of disease:
Target Ag: insulin receptor.
Mechanism of disease: Ab inhibits binding of insulin.
Serum sickness: acute and chronic types
Hypersensitivity type:
Acute form classically due to non-human protein Ag (diphtheria antitoxin).
Chronic form is from self-Ags (lupus, etc.).
Type 3.
Arthus reaction
Hypersensitivity type:
Seen in rabbits injected w/ horse serum.
Rare local effect of vaccination.
Type 3.
How does post-streptococcal cross-reactive Abs act at the heart versus the kidneys?
Heart - cross-reactive Abs directly act on myocardium -> type 2.
Kidneys - cross-reactive Abs are forming immune complexes that deposit in the glomeruli -> type 3.
T1DM is what hypersensitivity?
Type 4.
Examples of type 4 hypersensitivities (6)
RA MS T1DM IBD Psoriasis Contact dermatitis
Tuberculin skin test (4 steps)
What does it indicate?
PPD is intradermally injected.
Reaction is reassessed 48-72 hrs later.
Sensitized T cells begin inflammatory response.
Local swelling results.
Indicates prior TB exposure.
What happens to self-reactive T cells in the thymus?
What happens to self-reactive B cells in the bone marrow?
Apoptosis.
Can undergo receptor editing or apoptosis.
What can happen to the T cells that are self-reactive in the periphery? (2)
Anergy
Suppression by Tregs.
2 inhibitory receptors in T cells
What do they do?
Who takes advantage of this?
CTLA, PD-1.
Help T cells downregulate when self-Ags are presented.
Tumors and viruses can utilize this to evade immune destruction.
How does blocking the action of CTLA and PD-1 w/ Abs affect cancer cells?
The immune response becomes amplified against the cancer cells.
Most common Tregs are induced by:
Positive for:
Express: (2)
Induced by TGF-beta.
Positive for CD4.
Express CD25 and FOXP3*.
What are 2 actions of Treg cells?
Cytokine immunosuppression (IL-10, TGF-beta). Inhibition by CTLA-4.
How can Tregs suppress naive T cell activation?
They block and move B7 on APCs (which would bind CD28 on naive T cells)
Mutations in the AIRE gene can lead to:
Polyendocrine disorders due to autoimmunity.
IPEX can cause:
Systemic disease in humans
3 characteristics of defining an autoimmune disease
The immune reaction is directed against a self-Ag.
The immune reaction is primarily responsible for a pathologic condition.
No other pathophysiology is responsible.
Ankylosing spondylitis
What is it associated with?
Hereditary inflammatory condition of the joints of the spine.
Inflammation leads to degeneration and then fusion of the vertebrae.
Class I HLA allele B27, but it is not definitive of having or not having the disease.
Crohn disease cause:
What does it lead to?
Polymorphisms in NOD-2 gene that renders Paneth cells in intestinal epithelium ineffective at micorbial killing.
Defective killing and clearance leads to accumulation of bacteria and an exaggerated immune response.
What is the initial T cell response in Oral Lichen Planus? What is epitope spreading?
Initial T cell response leads to keratonic lesions in oral and conjunctival mucosa.
Epitope spreading occurs when the basement membrane disruption exposes antigenic proteins which leads to a secondary B cell response.
ANA can be used to detect: (3)
What does its presence prompt?
Systemic lupus erythematosus (discoid lupus, drug-induced lupus).
Sjogren syndrome
Systemic sclerosis
More specific testing to confirm the diagnosis.
What tests are most specific for people with lupus? (2)
Anti DS DNA
Anti Smith
What tests are most specific for people with Sjogren’s? (2)
Anti Ro/SS-A
Anti La/SS-B
What tests is most specific for people with systemic sclerosis? (1)
Anti DNA topoisomerase
What are 3 genetic and environmental influences that degrade self-tolerance in SLE?
Genetic association: familial patterns, HLA-DQ.
Female bias: X chr.
UV light
Immune cells/complexes involved in SLE (3)
B cells
CD4+ T cells
Immune complex formation
To call it SLE, ___ characteristics of a list including which criteria? (11)
4.
Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal d/o Neurological d/o Hematologic d/o Immunologic d/o Antinuclear antibodies
When should you suspect Lupus?
Younger females.
Arthritis, skin rahses, fevers, fatigue, hemolytic anemia, edema.
What occurs first in Lupus Nephritis?
What happens last?
What is seen often as an end-stage process?
Minimal mesangial.
Sclerosing lupus nephritis.
Fibrosis.
Diffuse Lupus Nephritis (class IV)
Sx:
The glomeruli show:
Type of hypersensitivity?
Most common pattern of lupus nephritis.
Pts are symptomatic (hematuria and proteinuria).
Glomeruli show increased cellularity.
- proliferation of endothelial, mesangial and epithelial cells.
- EM shows immune deposits in subendothelium.
Type 3, granular pattern of IgG Ab-containing complexes.
What happens in the skin changes in SLE?
Basal layer degenerates leaving vacuolated spaces between degenerating cells.
Positive immunofluorescence.
Libman-Sacks endocaditis
A CV complication from SLE.
Contains “verrucuos” (warty) valve deposits composed of fibrin.
Not infective.
Rarely embolize, but can happrn.
What are 2 CV complications from SLE?
Libman-Sacks endocarditis
CAD
What is an L-E cell?
A neutrophil or Mo that ingests the nucleus of a damaged cell.
Not used for DX anymore, but may be seen in blood or body fluids.
Discoid lupus erythematosis includes what 3 characteristics?
Discoid rash
Positive ANA
Positive immunofluorescence
Discoid lupus affects what area of body?
What tests are positive and negative?
What is possible from its onset?
Usually only affects face and scalp.
Positive ANA.
Negative Anti-DS DNA.
Progression is possible.
- disseminated skin lesions.
- systemic organ involvement (late occurrence)
Drug-induced lupus (DIL) cause:
What meds? (2)
What is positive? (2)
Does it resolve?
Medication-induced breakdown of self-tolerance.
Procainamide, Hydralazine.
Positive ANA (arthralgias, fever), anti-histone Ab.
Yes, once the meds stop.
HLA high-risk linkages in drug-induced lupus for Hydralazine and Procainamide
Hydralazine: HLA-DR4
Procainamide: HLA-DR6
What happens in Sjogren syndrome (generally)?
Destruction of lacrimal and salivary gland tissue
What is the pathogenesis of Sjogren syndrome?
B and T cell mediated inflammatory reaction to target tissues with inflammatory damage followed by fibrotic destruction.
Major sx of Sjogren syndrome (3)
Dry eyes
Root caries
Smooth tongue w/ candida infection from dry mouth
What test evaluates for tear production?
Schirmer’s test
How is Sjogren syndrome diagnosed? (2)
Anti-Ro/SS-A and Anti-La/SS-B
Bx of lip to look for inflammation of minor salivary glands.
What are some complications of Sjogren syndrome?
Extraglandular disease: pulmonary fibrosis.
Lymphoid proliferation becoming clonal: Lymphoma*
What triggers the following pathways?
Alternate
Classical
Lectin
Alternate - microbe/pathogen
Classical - antibody
Lectin - mannose binding lectin (MBL)
Roles of C3b and C5a/C3a
C3b: phagocytosis
C5a/C3a: inflammation
Which cytokines are essential for class switching?
IL-4 and IFN-y
Immediate response from PGD2 and LTB, C, D in allergy:
Bronchoconstriction
Increased bowel peristalsis
Vascular leakeage
Role of the doctor after allergen is identified (2):
Block His and provide airway support
Which hypersensitivities are insulin resistant DM vs T1DM?
Insulin resistant DM: type 2
T1DM: type 4
Type 2 hypersensitivity
Abs react w/ Ags on cells or ECM
Type 3 hypersensitivity
Ab-Ab complexes form and cause damage
Fluoresence for type 2 vs type 3
Type 2 is smooth/liner
Type 3 is grainy/granular
Hypersensitivity for Goodpasture syndrome
Type 2
ANA patterns for:
SLE:
Centromere:
Systemic sclerosis:
Sjogren syndrome:
SLE: speckled, but can be homogenous, rim/peripheral or nuclear.
Centromere: CREST syndrome
Systemic sclerosis: speckled
Sjogren syndrome: speckled
