Pathology of Immunity Part 1 Flashcards
When the B cell becomes activated, what happens?
where do these processes mostly occur? how do the B cells get to these places and what are they called?
undergo HEAVY-chain class switching and affinity maturation (producing antibodies with high affinity for the antigen)
germinal centers in secondary lymphoid organs (LN or spleen) –> T cells help them migrate there and are called “follicular Helper T cells”
What are the different barriers of the innate immunity before alerting cells?
there are 5.
Epithelia of the skin –> mechanical barrier + antimicrobial molecules (ex = defensins))
Salivary glands –> secretions cleanse the oral cavity
Tears
Ciliated epithelium in the lungs traps and sweeps inhaled pathogens
Acid pH of stomach kills microorganisms.
Why is antigen receptor gene rearrangement and clonality important for testing?
Because each T or B cell and its clonal progeny have unique antigen receptor, it’s possible to distinguish polyclonal (nonneoplastic) lymphocyte proliferations from monoclonal (neoplastic) lymphoid tumors
What are innate lymphoid cells generally?
what is the first defined ILC?
what 3 things do ILCs do?
lymphocytes that lack TCRs but produce cytokines similar to those made by T cells
NK cells
1) early defense against infection
2) recognition and elimination of stressed cells (stress surveillance)
3) shaping later adaptive immune response through providing cytokines that help induce differentiation
What is immunologic tolerance?
What is Self tolerance?
unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen
Lack of responsiveness to an individual’s OWN antigens –> it’s the main reason why we don’t kill our own tissues
What’s the first Lupus Nephritis that happens?
what’s last?
when is fibrosis seen?
what is the most common?
Minimal Mesangial (class 1)
Advanced Sclerosing Lupus Nephritis (Class 6)
Sclerosing
Diffuse Lupus nephritis
Explain C-type lectin receptors (CLRs)
1) where are they found?
2) what do they detect?
CLRs are expressed on PLASMA MEMBRANES of MACROPHAGES and DENDRITIC CELLS
detect fungal glycans and elicit inflammatory reactions to fungi.
Why might someone with Sjogren have trouble swallowing?
What do they have that would indicate a diagnosis for Sjorgrens?
Why might a biopsy of the lip be helpful?
what 2 complications can be seen in people with sjogren syndrome?
dry mouth –> hard to swallow
ANA +, Anti-Ro/SS-A, and Anti-La/SS-B
you can look for inflammation of minor salivary gland tissue
Extraglandular disease: pulmonary fibrosis
lymphoid proliferation becoming clonal and leading to lymphoma!!
What do 100% of patients have clinically? what about 80-90%
other clinical symptoms?
Hematologic problems like Hemolytic anemia
Arthritis
Skin Rashes
Fever,
fatigue
Edema
What are the only cells in the body that contain antigen receptor genes that have RECOMBINED?
T and B cells
What constitutes Discoid Lupus Erythematosus?
what would be negative in testing?
Where do we see the problems clinically?
is progression possible?
Discoid Rash, Positive ANA, Positive Immunofluorescence
Negative Anti-DS DNA
typically the face and scalp are having disseminated skin lesions.
yes, 5-10% can have late occurrence systemic organ involvement –> like renal manifestations.
B cells: when they’re stimulated by antigen and other signals, what happens?
what are the different products it makes and what does each do?
which one is the biggest?
which has high levels in the colostrum? what is that?
which has the longest half life? what is important with?
which has the shortest half life? what does it do? what does it have high affinity binding to?
become plasma cells that make antibodies
IgM –> the FIRST Ig produced. It’s a pentamer (HUGE)
IgA –> Mucosal defense, present in high levels in the colostrum (1st breast milk)
IgG –> longest half life, important in fetal protection (can cross)
IgE –> shortest half life, regulates hypersensitivity reactions… Fc receptors on Mast, basophils, eosinophils
Cell-Mediated Immunity:
1) what are the two possible differentiations and how does it happen?
2) what is the end result of each?
1)
MHC I (presents peptides derived from proteins located in the cytoplasm and produced in the cell–> CD8 T cell –> KILLING of INTRACELLULAR pathogens
MHC II (present antigens derived from extracellular microbes that are internalized into vesicles –> CD4 T cell –> RECRUITMENT of macrophages and other T lymphocytes to take care of it!
Memory cells –> important for re-exposure
AIRE gene mutations:
1) what is the purpose of AIRE, and where does it exert its normal function?
2) what normal process would fail in the absence of normal AIRE?
1) It stimulates the expression of some “peripheral-tissue-restricted” self antigens in the THYMUS and is CRITICAL for deletion of immature T cells specific for these antigens
2) no AIRE or mutations in it, no expression of some subsets of self-antigen, so they can see self antigens in the thymus and develop into Treg cells and leave.
1) What are pattern recognition receptors a part of?
2) Where are pattern recognition receptors located?
3) what are the best known pattern recognition receptors?
4) this specific receptor, where is it found on? what do all of them end up doing?
INNATE immune system
all cellular compartments where microbes may be present –> plasma membrane, endosomal, cytoplasmic.
Toll Like Receptors –> Present on plasma membrane and endosomal vesicles.
they end up activating 2 sets of transcription factors –> NF-,B (makes more cytokines and expresses adhesion molecules) and INTERFERON REGULATORY FACTORS (IRFs) (create type 1 interferons which are anti-viral cytokines)
PTPN22:
1) what does it encode?
2) polymorphisms in this gene are associated with what diseases?
It encodes protein tyrosine phosphatase
RA, T1DM, and others
sadi to be a gene most frequently implicated in autoimmunity
What is Scleroderma?
what makes it unique?
What two things do you see on histo stains?
What eventually does Scleroderma progress to?
Fibrosis through the body: skin, GI, kidney, heart, lung
Can be part of the CREST syndrome
dense collagenous deposition consistent with subcutaneous fibrosis. You also see vascular hyalinization
Reynauds –> cold, ischemic fingers that become necrotic and DISTAL phalangeal bone undergoes ISCHEMIC RESORPTION
Sclerodactyly –> thickening, tightening of the skin on the fingers and hands
In the innate immune response, what cytokines are released? when are they released? 6
what is their main function overall?
they are released rapidly
TNF, IL1, IL-12, Type 1 INFs, IFN-gamma, chemokines
induce inflammation and inhibit viral replication
What are the main components of the Innate immunity?
1) broadly, what are the 3 things that are part of it?
2) First line?
3) what happens if #2 is breached? What are the cell types in this process? what do they do broadly?
4) What is not a cell type but is still part of the innate immunity? how are they activated in the innate immune system?
5) what about the adaptive immunity and #5?
1) Barrier defense, Cells, Proteins
2) Barrier defense is the first line
3) If breached:
neutrophils and monocytes (monocytes that enter tissues = macrophages)
Dendritic cells –> capture protein antigens and display peptides for recognition by T lymphocytes
NK cells –> early protection against viruses and intracellular bacteria
Mast cells –> produce mediators of inflammation
4) Complement proteins –> activated by microbes using alternative and lectin pathway
5) classical pathway!
Diffuse Lupus Nephritis (Class IV):
1) what should you know about this?
2) what symptoms do patients present with?
3) what would you see in the glomeruli?
4) what do you see on EM?
5) what would you see on a immunofluorescence staining? what does this mean?
it’s the most common pattern of lupus nephritis
proteinuria, hematuria –> which leads to ankle swelling because of the loss of protein.
increased cellularity –> proliferation of endothelial, mesangial, and epithelial cells
immune deposits IN the sub endothelium.. which are called “wire loops”.
granular pattern of IgG antibody containing complexes –> type 3 hypersensitivity!!!
What is peripheral tolerance?
What mechanisms happen within peripheral tolerance?
Peripheral tolerance –> silencing potentially auto regulative T and B cells in PERIPHERAL tissues.
Anergy –> lymphocytes that recognize self antigens are rendered functionally unresponsive… when they recognize self, they receive INHIBITORY SIGNALS from receptors that are homologous to CD28 –> CTLA-4 and PD-1 –> leads to anergy
Treg cell Suppresion –> Treg cells prevent immune reactions against self antigens through CTLA4 inhibition and cytokine immunosuppression IL-10 and TGF-B
What are colony (hematopoietic) factors?
where do they come from?
what is their function?
examples?
they stimulate formation of blood cell colonies from BONE MARROW progenitors.
increase leukocyte numbers during immune/inflammatory responses.
CSFs –> GM-CSF and IL-7
What cell would you see histologically that would lead you to think it’s SLE?
L-E cell
a neutrophil or macrophage that ingests the nucleus of a damaged cell –> cells’ nucleus is squashing the neutrophil so it looks like a completely full neutrophil
Cell-Mediated immunity:
1) what is the process from capture of the antigen to recognition by the cell? (include both signals and be specific)
2) what type of pathogen is part of this process?
3) what happens once they are “activated” by the signals?
1) Dendritic cells capture antigens from epithelia and tissues –> go to lymph nodes and express high levels of MHC with the antigen (signal 1) which binds to the TCR
and costimulators (signal 2) (B7 proteins CD80 and CD86) –> B7 proteins are recognized by CD28 on the T cell.
2) intracellular
3) they proliferate and differentiate to effector cells –> migrate to the site needed and do their job
Type 1 Hypersensitivity:
What signals mast cells to release their contents?
On second exposure, what are mast cells releasing? (4 major groups of things with things in each) –> include the 3 main things that are characterized in the immediate reaction!
when are mast cells doing this?
Cross linking IgE Fc Receptors + anaphylatoxins (C3a and C5a), some drugs, and physical stimuli (heat, cold, sunlight)
1) Degranulation –> histamine and proteases
Lipid mediators:
2) arachidonic acid metabolites –> Leukotrienes B4,C4,D4 + Prostaglanding D2 –> vasodilation, vascular leakage, smooth muscle spasm
3) Platelet activating factor
4) Cytokines and Chemokines for LATE PHASE REACTION
this is the immediate response, NOT the late response.
Why would a granuloma be considered a type 4 response?
immune granulomas are caused by agents that are capable of inducing a persistent T CELL MEDIATED immune response
Type II hypersensitivity reaction:
1) what is going on in this one?
2) what are the antibodies targeting?
antibodies that react with antigens present on cell surfaces or in the ECM cause disease by destroying these cells, triggering inflammation, or interfering with normal function.
the antibodies might be targeting normal cells (autoantibodies) or exogenous antigens like chemical or microbial proteins
why are Treg cells important for the fetus?
for the baby to survive, regulatory T cells have to suppress the MATERNAL response to allow the fetus to survive and grow
this is because the fetus expresses paternal antigens that are foreign and haven’t been tolerated by the mom yet.
SLE:
1) What are the associated antibodies with SLE? what does this look like in the ANA staining?
2) what is it often associated with genetically?
3) who is it more associated with?
4) what are the clinical manifestations of the disease?
1) ANAs, (Antinuclear antibodies) –> these are directed against nuclear antigens and can be grouped int oa bunch of different categories
people with lupus have anti-DS-DNA and Anti Smith –> HOMOGENOUS
2) HLA-DQ
3) younger females
4) Malar (butterfly) rash, Discoid (scarring, hypo pigmented rash)
IPEX syndrome:
1) what does it stand for?
2) what mutation is involved?
3) what normal process fails in this disease?
Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked
Mutation in FOXP3
FOXP3 is required for the development and maintenance of functional CD4+ Treg cells!
RESULTS IN SEVERE MULTI-Organ autoimmunity
What is to note about post-streptococcus in the heart vs in the kidney?
in the heart, it directly acts on the myocardium as a type 2 reaction
in the kidney, the cross-reactive antibodies form immune complexes that deposit in the glomeruli –> type 3.
The following diseases are type 4, T cell mediated reactions. Explain their principal mechanism of injury, and the clinicopathologic manifestations
Rheumatoid arthritis
MS
Type 1 DM
IBD
Psoriasis
Contact Sensitivity
inflammation mediated by Th17 (and Th1) cytokines –> chronic arthritis with inflammation, destruction of articular cartilage
inflammation mediated by TH17 and TH1 –> demyelination in CNS (by macrophages), paralysis
T cell mediated inflammation and destruction of islet cells by CTLs –> Insulitis, destruction of Beta cells, diabetes
Th1 and Th17 –> chronic intestinal inflammation
TH17 mostly –> destructive plaques in the skin
TH1 (and Th17?) –> epidermal necrosis, dermal inflammation, skin rash/blisters
What are the three diseases to know about Type 2 hypersensitivities that creates cellular dysfunction?
what is specifically happening? what’s being targeted?
What does each present with clinically?
Myasthenia graves –> antibody inhibits acetylcholine binding by targeting the acetylcholine receptor and down-modulating it –> muscle weakness and paralysis
Graves Disease –> antibody STIMULATION of TSH receptors leading to hyperthyroidism
Insulin-resistant diabetes (TYPE 2) –> antibody inhibits binding of insulin on the insulin receptor –> hyperglycemia and ketoacidosis
