Immunity, Autoimmune disease, Immunodeficiency Flashcards
PBVD Ch. 5, R&C Ch. 6
What antimicrobial molecules do epithelia produce?
Defensins
What is the role of Innate Lymphoid Cells? Example?
Tissue resident lymphocytes that are activated by cytokines and are a source of cytokines in early immune reactions; NK cell
Which complement pathways are part of innate immunity? adaptive?
Lectin and alternative; classical (Ab-Ag complexes)
What proteins of innate immunity coat microbes and promote phagocytosis (not complement)
Mannose binding lectin and C-reactive protein
Receptor for IgG coated cells that stimulate Antibody dependent cellular cytotoxicity
Fc receptor (CD16) on NK cells
Two transcription factors activated by TLRs
NF-kappaB that stimulate release of cytokines and expression of adhesion molecules
IRFs (interferon regulatory factors) that stimulate production of type I interferons
Cytosolic receptors and their signals
NOD-like receptors- damaged cell products, microbial products
RIG-like receptors- viral RNA
How do NOD-like receptors work?
Bind to caspase 1, forms the inflammasome, activates caspase 1, which cleaves precursor IL-1
Role of IL-1
Recruits leukocytes and induces fever
Cell membrane receptors and their signals
C-type lectin- fungal glycans
TLRs- many
What molecule do neutrophils use G protein-coupled receptors to chemotax toward bacteria?
N-formylmethionine
What do NK cells produce upon activation? What inhibits their activation?
IFN-gamma- activates macrophages
Inhibitory receptors recognize MHC I
What cytokines stimulate NK cell proliferation?
IL-2 and IL-15
What cytokine stimulates NK cells to kill and secrete IFN gamma
IL-12
Enzyme in lymphocytes involved in somatic recombination and antigen receptor diversity
RAG1 and RAG2
What are the components of a T cell receptor; what is it linked to? Other two parts of the complex?
Alpha and beta chain heterodimer, each with a variable region
Linked to CD3 complex- 6 invariable proteins
CD4 or 8- coreceptors (binds MHCII or I)
CD28- 2nd signal (binds CD80 or CD86/B7)
What makes up the B cell receptor? Other parts of the complex?
IgM and IgD membrane bound antibodies
Heterodimer of two invariant proteins (Igalpha and Igbeta) aka CD79 a and b
Type 2 complement receptor (CR2 aka CD21)- recognize complement
CD40- bind CD40L on T helper cell
Features of follicular dendritic cells
In germinal centers
Bear Fc receptors for IgG and receptors for C3b
Present antigens to B cells, become plasma or memory cells
Most important APC for T cell response
Dendritic cells
Three jobs of macrophages
APC for T cell response
Activated by T cells to kill infected cells?
Phagocytose and destroy microbes opsonized by IgG or C3b (humoral)
Which cells express CD40?
Macrophages and B cells
What molecules stimulate IgM production?
Polysaccharides and lipids
What molecules stimulate IgG, IgA, or IgE production?
Proteins via CD40L and helper T cells (isotype switching)
What induces isotype switching of antibodies?
T cells producing IFNgamma and IL4
What do IgG and IgM do? What else does IgG do?
Activate classical complement; opsonize microbes for recognition by APCs with Fc receptors for IgG
What special thing does IgA do? IgE? IgG?
Mucosal immunity; mast cell and eosinophil activation (allergy); newborn immunity
Who expresses MHC Class I? Components? What two components bind antigen? What site binds CD8?
Nucleated cells and platelets; Alpha heavy chain (1, 2, 3) and beta2 microglobulin; alpha1 and alpha 2; alpha3
Who expresses MHC Class II? Components? What two components bind antigen? What site binds CD4?
APCs, B lymphocytes; alpha (1 and 2) and beta (1 and 2) heavy chains; alpha 1 and beta 1; beta2
Main source of cytokines in adaptive immunity
CD4+ T lymphocytes
Cytokines that serve to terminate immune response
TGF-beta and IL-10
What stimulates affinity maturation?
Helper T cells, follicular type, in germinal centers
What type of T cell response causes Type I hypersensitivity? Cells and molecules involved; example?
Th2; IgE, mast cells; allergy, anaphylaxis
What sensitizes mast cells? What activates mast cells? Other causes of mast cell activation
IgE; Crosslinking of IgE; C5a, C3a, IL-8, drugs (codeine, adenosine, bee venom), physical stimuli (heat, cold, sunlight)
What from eosinophils contributes to type I HS
Major Basic Protein
Most sensitive species to anaphylaxis?
Guinea pigs
Immediate type I hypersensitivity features; late-phase features
Vasodilation, congestion, edema; inflammatory infiltrate of eos, neutrophils, T cells
What receptor does IgE bind to on mast cells?
FcepsilonRI
How is ADCC different from opsonization and phagocytosis via IgG and IgM
No phagocytosis, NK cells and macrophages kill cells coated in antibody whereas opsonization activates complement and phagocytosis
What mediates Type II HS?
Secreted IgG and IgM antibodies then ADCC, opsonization, phagocytosis,
Examples of Type II HS?
IMHA, pemphigus, drug reactions, transfusion reactions
Example of Type II HS due to cellular dysfunction, not inflammation
Myasthenia gravis- Abs interfere with function of Ach receptors
What mediates Type III HS?
Ab-Ag complexes, IgG and IgM, activate complement, phagocytosis, platelet aggregation, coag factors
Examples of Type III HS?
SLE, glomerulonephritis, vasculitis, arthritis
What mediates Type IV HS?
Cytokines produced by CD4+ T cells, aka cell-mediated, Th1 (macrophage dominated) and Th17 (neutrophil dominated) cells; can also be CD8 direct cytolysis
Examples of Type IV HS?
Tuberculosis, Equine recurrent uveitis, rheumatoid arthritis, poison ivy, allergic contact dermatitis (haptens)
Link between type III HS and coag cascade
Complexes activate factor XII (Hageman factor), which activates kinins and causes vasodilation and edema
How do CD8+ T cells kill cells?
Release granzymes, perforins into immunologic synapse, and express Fas ligand to also induce apoptosis
Where does central tolerance occur for T cells? B cells?
Thymus; bone marrow
What is central tolerance for T cells?
Positive selection for T cells that recognize MHC; Negative selection of T cells that recognize self antigen bound to MHC
What protein mediates expression of self-antigens in the thymus for negative selection?
Autoimmune regulator (AIRE)
What happens to T cells that are self-reactive in the thymus?
Undergo apoptosis via Fas-FasL
Become Treg cells
Escape
What happens to B cells that are self-reactive?
Antigen receptor gene rearrangement- receptor editing
Apoptosis
What is peripheral tolerance?
Back up system in case self-reactive cells escape central tolerance
What three mechanisms of peripheral tolerance are there?
Anergy
Treg suppression
Deletion by apoptosis
What causes anergy of T cells (2)? B cells?
Self-reactive T cell presented with self-antigen, and does not receive second signal, or receives inhibitory signal from CTLA-4; No CD40L from Th cells
Features of regulatory T cells
CD4+
Express CD25 (IL-2 receptor)- require IL-2
FOXP3
Secrete IL-10 and TGFbeta
Mechanisms of apoptosis in peripheral tolerance
Unopposed Bim expression
Activation induced cell death- if persistently activated, express Fas
What is the hallmark of SLE?
Production of autoantibodies (ANAs, IgGs)
What type of HS is SLE?
Type III
What MHC allele is SLE associated with in dogs? ANAs usually against?
DLA-A7; Histones
Arms of immunity involved in SLE
Humoral and cellular- Too many CD4 cells and too many self-reactive B cells
Clin path findings with SLE
Lymphopenia with high CD4:CD8 ratio
What are LE cells?
Phagocytes that have engulfed an LE body, which are ANAs on free nuclei
What is Sjogren-like syndrome? Presentation in cats? In dogs?
KCS, xerostomia, sialoadenitis; Lymphoplasmacytic sialoadenitis with primarily B cells; KCS with primarily CD4+ T cells and hypergammaglobulinemia
What type of HS is juvenile polyarteritis?
Beagle pain syndrome- type III
Immunologic features with beagle pain syndrome?
IL-6 (stimulates B cells) and IgA elevated, ANA negative
Direct transplant rejection
Donor APCs present antigen to recipient T cells- CD8+ response, acute
Indirect transplant rejection
Recipient APCs present antigen to recipient T cells- antibody production, chronic
Three examples of innate immunodeficiencies
Leukocyte adhesion deficiency
Chediak-Higashi Syndrome
Complement deficiencies
What is Type I LAD?
Mutations in Beta2 chain subunits of CD18/CD11 integrins (on LFA-1, MAC-1, CR-2), so can’t bind ICAMs on endothelium
What is Type II LAD?
Can’t synthesize sialyl-Lewis X, so can’t interact with E- or P-selectins on endothelium
Cause of Chediak-Higashi
Autosomal recessive LYST gene mutation, so can’t fuse lysosomes and phagosomes
Clinical presentation of Chediak- Higashi
Enlarged granules, impaired immunity, hypopigmentation, coagulopathy
Most common complement deficiency; least severe one? Associated with what?
C2; C2; SLE- can’t clear immune complexes
Most severe complement deficiency; what breed?
C3; Brittany spaniels get autosomal recessive deficiency
What happens with a Factor H deficiency? Who gets it?
C3b excess accumulation; Norwegian Yorkshire pigs, end up with type II membranoproliferative glomerulonephritis
SCID heritability; cells affected
X-linked or autosomal recessive; T or B cells, or both
Who is predisposed to X-linked SCID; pathogenesis
Males, Bassett hounds, Welsh corgis; Mutation in gamma subunit of cytokine receptors, so no mature T lymphocytes, and then no B cells activated
Who is predisposed to autosomal recessive SCID?
Arabian foals, CB-17 mice
Can’t produce variable region of antibody or antigen receptor, so no functional T or B cells
Other causes of autosomal recessive SCID?
Deficiency in adenosine deaminase (ADA), so accumulate deoxyadenosine, which is toxic to T cells
Deficiency in RAG gene, so can’t do somatic gene rearrangement
What is agammaglobulinemia?
Who gets it? Heritability?
B cell precursors can’t mature; Horses; X-linked
What is DiGeorge Syndrome?
Thymic hypoplasia, failure of development of 3rd and 4th pharyngeal pouch, so no T cells
Who gets an IgA deficiency?
GSDs, Shar-peis, Irish setters, beagles
Who gets a hyper-IgM syndrome? Cause?
Humans, dogs, horses; Mutation in CD40L, preventing class switching
What does HIV target?
CD4+ T cells
What are the two HIV glycoproteins? Where are they and what do they do?
gp120- surface, binds CD4, then CCR5
gp41- transmembrane, membrane fusion and release of RNA into cell
How does HIV work once viral genome enters cell?
viral RNA uses it’s own reverse transcriptase to form cytoplasmic DNA, which chills until the cell divides, then enters the genome. Chills there until cytokine activation, then replication and shedding, cell lysis
Why can’t HIV infect naive T cells?
APOBEC3G enzyme mutates viral DNA
gag gene function
Polyprotein that forms matrix protein (p17), capsid protein (p24), nucleocapsid protein (p7)
pol gene function
Polymerase that forms protease, reverse transcriptase, etc.
env gene function
gp160 envelope protein, cleaved into gp120 and gp41
What transcription factor stimulates transcription of virus upon activation of T cells; how?
NFkappaB; HIV genome has NFkappaB binding sites
How does HIV cause recruitment of other inflammatory cells?
Inflammasome activation and pyroptosis
Why does HIV cause syncytia?
gp120 expression on infected cells
What other cells does HIV infect, but doesnt kill?
Macrophages/monocytes, microglia, dendritic cells
What cell types are not infected by HIV
Neurons, B cells, CD8+ T cells
