Robbins Chapter 6: Hypersensitivity and Autoimmune Diseases Flashcards
What are the 3 pathways of Complement and what are their 3 effector functions?
Pathways: Alternate (microbe), Classical (IgG/M), Lectin (Mannose-binding lectin)
Effector functions:
- C3a, C5a = inflammation
- C3b = phagocytosis
- MAC - lysis of microbe
What are the spleen and mucosa-associated lymph tissue (MALT) important in adaptive immunity?
spleen - lymphocyte interaction w/blood-borne Ags
MALT - lymphocytes/plasma cells proximity to mouth and intestinal tract
Thymus - T-cell Training
medulla contains maturing T lymphocytes (arrive from bone marrow) that migrate from the cortex to the central medulla
many dendritic APCs are found in the medulla
Where do T and B cells predominately hang out at in the Lymph Nodes?
T-cells –> paracortex
B-cells –> germinal centers
Difference between MHC I and II presentation
MHC I
- Ags processed by PROTEASOME (intracellular Ags)
- endoplasmic reticulum
MHC II
- Ags processed by Endolysosomal enzymes (Extra)
- vesicles form with MHC II and peptide
What chromosome encodes for MHC and what are the 6 alleles?
Chromosome 6
Class I alleles = A, B, C
Class II alleles = DR, DQ, DP
What two major functions of the Humoral Response are performed by T-cell dependent actions?
isotype switching and increasing affinity of Abs
Ab characteristics (IgM, IgG, IgA, IgE)
IgM - first produced (pentameter –> YUGE)
IgG - longest half life, fetal protection
IgA - mucosal defense, hi lvls in colostrum (1st milk)
IgE - shortest half life, hypersensitivity rxns
What inhibits and activates Natural Killer Cells?
- INNATE immune cells (no TCR or Ig)
Inhib by: self MHC molecules or Class I MHC
Active by: damaged cells (NKG2D receptors)
Type I Hypersensitivity (cells and ILs)
- Th2 cells cause B cell switch to IgE (bind to mast cell)
- IL-4 (switch), IL-5 (eosinophil), IL-13 (inc. IgE prod)
- first exposure causes the development of primed IgE/mast cell complexes, with subsequent exposures producing symptoms of Type 1 Hypersensitivity
What is the difference between the Immediate Reaction and Late Phase Reaction of Type I Hypersensitivity?
Immediate
- mast cell mediators
- vasodilation, vascular leakage, SM spasms
Late Phase
- inflammatory cells (eosinophil, basophil, neutrophil)
- epithelial damage
What is Eosinophilic Esophagitis?
food antigen-driven disease of childhood that causes recurrent dysphagia (late phase reaction)
- see weight loss due to not swallowing effectively and pain
What causes Autoimmune Hemolytic Anemia and Thombocytopenia purpura?
TYPE 2 HYPERSENSITIVITY
- antibodies target RBC and platelet membrane proteins, causing opsonization and phagocytosis
What is the mechanism of disease caused by Vasculitis (ANCA), Goodpasture Syndrome, and Acute Rheumatic Fever?
TYPE 2 HYPERSENSITIVITY
V - neutrophil degranulation and inflammation
GS - complement/Fc-mediated inflammation
ARF - inflammation and macrophage activation
Why is Streptococcal Antigen important in Rheumatic Fever? (3 symptoms)
generation of CROSS REACTIVE antibodies
Strep. antigens have molecular mimicry with myocardial antigen, meaning Abs generated against infection can also damage the heart
- vegetations, Aschoff body in myocardium, fibrinous pericardium
What causes Myasthenia Gravis, Graves Disease, and Insulin-resistant Diabetes?
TYPE 2 HYPERSENSITIVITY
MG - Abs inhibit Acetylcholine binding to receptors
GD - Abs stimulate TSH receptor
IRD - Abs inhibit insulin binding to receptors
What does a smooth/linear vs grainy/granular immunofluorescence kidney biopsy mean?
Smooth and linear –> Type II Hypersensitivity
- Good Pasture (anti-basement membrane Ab)
Grainy and granular –> Type III Hypersensitivity
- Lupus Nephritis (immune complex disease)
What is a common hallmark of Type IV Hypersensitivity reactions?
Granuloma formation
What two inhibitory receptors are important for T lymphocyte anergy?
CTLA and PD-1
- some tumors/viruses can use these to evade immune destruction
- can use Abs to block these receptors to drive T cell responses against viruses and tumors that would normally upregulate these receptors to stay hidden
What is Ankylosing Spondylitis? What allele is it associated with?
AUTOIMMUNE DISEASE (young male w/back pain)
- hereditary joint inflammatory disease of the spine (degeneration and fusion)
- strongly associated with HLA Class I B27 allele
What is Crohn’s Disease?
AUTOIMMUNE DISEASE
- NOD-2 gene polymorphisms cause Paneth cells to be ineffective at killing pathogens (bacteria accumulate)
- causes bacterial overgrowth and Fistula Formation
What is Oral Lichen Planus?
AUTOIMMUNE DISEASE
- T cells response causes keratotic lesions in oral and conjunctival mucosa. This disrupts the membrane exposing antigentic proteins causing a secondary B cell response
- secondary B cell response causes blistering in Secondary Pemphigoid
What test would you start with if you suspected a patient of having an Autoimmune Disease? What specific tests would you order to people with Lupus, Sjogren Syndrome, and Systemic Sclerosis?
ANA test –> looking for positive rxn (sensitive testing)
specific tests might not always be present
Lupus –> anti-DS DNA and anti-Smith
Sjogren –> Anti Ro/SS-A and anti La/SS-B
Sclerosis –> Anti DNA topoisomerase (Scl-70)
What 3 things put patients at greater risk for developing Systemic Lupus Erythematosus?
What are 2 rashes involved with this disease?
genes: family or HLA-DQ
female: x-chromosome bias
UV light
rashes: malar (butterfly) and discoid (hypopigmentation of face and scalp)
What are 6 symptoms of Lupus and which one is seen 100% of the time in patients with Lupus?
arthritis, skin rashes, fever, fatigue, hemolytic anemia, edema (IF renal involvement)
- Hemolytic Anemia is seen in 100% or patients
What is Diffuse Lupus Nephritis (Class IV)?
most common pattern of Lupus nephritis
- inc. cellularity in glomeruli with proteinuria and hematuria (immune deposits in the subendothelium)
- immune complex-mediated disease (Type III)
What are 2 common Cardiovascular complications of Lupus?
Libman-Sacks Endocarditis
- wart valve lesions of fibrin (NOT infective)
Coronary Artery Disease
- contribution from Anti-phospholipid Ab syndrome
What are L-E cells and what disease are they found in?
neutrophil or macrophage that has ingested the nucleus of a damaged cell, causing the nucleus of the immune cell to be pushed to the periphery
- can be see in blood or body fluids of patients with Lupus
What is Discoid Lupus and what are 3 positive findings of it?
- mainly affects face and scalp; (-) Anti-DS DNA test
- disseminated skin lesions of face and scalp
PF: discoid rash, positive ANA, positive immunofluorescence
What is Drug-induced Lupus Erythematosus and what are 5 positive findings of it?
- medication-induced breakdown of self tolerance that resolves with drug discontinuation
- positive Anti-HISTONE Ab
PF: arthralgias/fever, positive ANA, discoid rash, hematologic disease, positive immunofluorescence
What two drugs are common causes of Drug-induced Lupus and how do they cause it? (HP)
Hydralazine inc. risk in pts with HLA-DR4 allele
Procainamide inc. risk in pts with HLA-DR6 allele
What is Sjogrens Syndrome?
autoimmune disease causing lacrimal and salivary gland destruction (B and T cell mediated inflam. followed by fibrotic destruction)
- dry eyes (Schirmers test), inc. cavities, smooth tongue with candida infection (Oral Thrush)
What are two possible complications of Sjogrens Syndrome?
pulmonary fibrosis and lymphoma development
What is Systemic Sclerosis? What are two common physical finding of it?
- fibrosis throughout the body (mainly skin) showing dense collagenous deposition (subQ fibrosis)
- can be part of CREST syndrome (see a centromere ANA pattern)
physical exam: Sclerodactyly and Raynauds
What is Crest Syndrome?
unique form of limited sclerosis that has a better prognosis than diffuse sclerosis
C (calcinosis of skin), R (Raynauds), E (esophageal dysfunction), S (sclerodactyly), T (telangiectasias)
Hyperacute Graft Rejection
occurs within MINUTES to HOURS
- mediated by pre-formed Abs (ABO)
- marked inflammation followed by thrombotic microvasculopathy
Acute Antibody-mediated Graft Rejection
inflammation with complement C4d breakdown product
- stain for the C4d component (brown)
Chronic Antibody-mediated Graft Rejection
fibrosis with primary effect on vessels
- fibrosis stains blue
Acute Cellular Graft Rejection
T-cell mediated occuring within days, months, or years of transplant
- can tell the difference between it and Ab-mediated by LACK of C4d staining
How can we treat T and B cell graft rejection?
- CORTICOSTEROIDS (immunosuppressive)
T cell: tacrolimus
B cell: immune globulin, Rituximab (anti CD20)
What is Graft vs Host Disease and what are common symptoms of it? (Skin, Liver, Intestines)
T-lymphocyte mediated
Skin –> rash to desquamation
Liver –> jaundice to cholestasis
Intestines –> bloody diarrhea to strictures
What is Chediak Higashi Syndrome?
autorecessive –> failure of phagolysosomal fusion, causing inc. bacterial infections and is fatal w/o stem cell transplant
- giant granules and melanocyte defects (albinism or grey hair streaks)
What is Chronic Granulomatous Disease?
group of genetic disorders that fail to produce superoxide in phagocytes, resulting in granuloma formation
What infections are common in patients with MAC deficiency?
NEISSERIA that cause MENINGITIS
What is Hereditary Angioedema?
autodominant deficiency of C1 inhibitor (no C1 esterase inhibitor)
symptoms: throat constriction similar to anaphylactic rxn, intestinal swelling, swelling of face and extremities
What is Severe Combined Immunodeficiency (SCID)? (2 forms of inheritance)
deficiency of B and T cell lineages due to T cell function defect
- X-linked (IL receptor mutations, dec. T cells and B cells unable to make Abs)
- autorecessive (ADA deficiency causing toxic purine metabolite accumulation); NO T cell formation, B cells fine but don’t function right
How do you treat SCID? (2)
stem cell transplant and gene therapy (put corrected gene in a viral vector and give back to patient)
What is DiGeorge Syndrome?
T lymphocyte deficiency due to failure of pharyngeal pouches 3 and 4 (22q11 deletions)
- facial/palate abnormalities, cardiac abnormalities, tetany, immune deficiency
What is X-linked Agammaglobulinemia?
- defect in BTK gene on X chromosome (inability of pre-B cells to mature)
- inc. risk of infection after maternal Abs wane (inc. risk of incapsulated bacterial infections)
What is Hyper IgM Syndrome?
lack of opsonising antibodies due to CD40/40L mutations that prevent class switching
- inc. IgM lvls but every other Ig class is lower (inc. risk of encapsulated bacterial infections)
What is Common Variable Immunodeficiency (CVID)?
multiple disorders resulting in hypogammaglobulinemia (most common significant primary immunodeficiency)
disease of exclusion
- recurrent sinus/pulmonary infections, granulomas, chronic diarrhea, autoimmune disease
What is IgA deficiency?
less defense against inhaled and ingested pathogens
- inc. sinus/respiratory/urinary/gastrointestinal infections
- anaphylactic rxn against RBC transfusions (washing out IgA before giving blood can help prevent)
What is Wiskott Aldrich Syndrome and what is its common triad? (TER)
WASP gene mutation causing thrombocytopenia, eczema, and recurrent infections
- treat with stem cell transplant
What is Ataxia Telangiectasia?
neurodegenerative disease (presenting at young age) causing gait
- also see vascular malformation and immune deficiency of IgA and IgG
- autosomal recessive (ATM gene mutation: defective DNA repair)
What capsid protein of HIV is good to test for and what 2 glycoproteins are good targets for treatment?
Capsid - p24 antigen
Glycoproteins - gp120 and gp41
What do the LTR, gag, env, and pol regions of HIV encode?
LTR - transcription initiation (binds transcription factors)
gag - encodes proteins inside virus
env - encodes surface glycoproteins
pol - encodes viral enzymes
What are the 6 steps of HIV infection?
- HIV uses CD4 for receptor
- gp120 binds to CD4 (allows coreceptor binding)
- gp41 drill into host to insert viral genome
- reverse transcriptase synthesizes proviral DS DNA
- integrase inserts into host genome
- LTR triggered to initiate transcription
stimulation causes NF-kB release that initiates viral transcription instead of T cell upregulation
What 3 cells does HIV commonly hid in?
macrophages, dendritic cells, and microglia
How does HIV affect B lymphocytes?
proliferative response that can become clonal (lymphoma)
- impaired humoral immunity due to reduced isotype switching and reduction of Ab production
What are the first 3 detectable substances on HIV testing?
- viral RNA (Nucleic Acid Test or NAT) - day 10
- protein antigen p24 - day 15
- antibody to HIV - day 25
Why are viral set point and clinical latency important in HIV infections?
Viral Set Point
- end of inital viremic spike that may predict CD4 loss
- inc. set point = dec. length of latency period
Clinical Latency
- period of silent CD4 cell massacre
- may go years without symptoms
- CD4 count < 200 is AIDs defining condition
What is Pneumocytis jiroveci?
opportunistic fungal infection that is an AIDs-defining illness
What protozoa is most commonly associated with diarrhea in AIDS patients?
cryptosporidium
What is Kaposi Sarcoma?
vascular tumor associated with Human Herpesvirus 8 that is associated with AIDs
What 3 lymphomas are associated with AIDs?
hodgkins/non-hodgkins lymphomas, CNS lymphoma, primary effusion lymphoma
What is Amyloidosis?
mutations or incorrect misfolding of proteins leading to insoluble beta-pleated sheats
What 4 organs do amyloids tend to congregate at? How can you visualize the amyloids?
kidney (proteinuria/edema), heart (dysrhythmias), liver, and brain
if systemic, try diagnosing via abdominal fat pad biopsy
- when you see “bubblegum pink” deposits, can use Congo Red stain that will show “apple green” birefringence in the presence of amyloids under polarized light
