Immunology Flashcards
1ary vs 2ry lymph tissues?
1ary: bone marrow, thymus for maturation
2ary: all other lymphoid tissue: nodes, spleen, tonsils, MALT, GALT
Anatomy of lymph node - where are macrphoages, B, Ts
- medularry cords: macrophages, plasma cells
- paracortical area: T cells
- cortical area: B cells and germinal centres
Where are we most prone to infection and what structures are there to help?
tracts:
- gastrointestinal: tonsils and adenoids; peyer’s oatches, intestines have most lymphocytes in body
- resp
- urogenital
Macrophages?
- phagocytosis!
- apc
- repair
- secrete pro-inflamm cytokines
Neutrophil?
lots in blood; 1st line after epithelial/mast cells
- phagocytosis
- degranulation to kill
- NETs - form net with antimicrobial peptides to kill
- signal to recruit others
Eosinophils?
- kill ab-parasites
- in allergic rxns
Basophils?
- unknown
- similar to mast cells
- allergic rxns
Mast cells?
- release granules iwith vasoactive amines
- anaphalyxis, type 1 hypersen
What are TLRs?
toll like receptors
- pathogen-associated molecular pattern receptors on cells
- each TLR recog one type of microbial component
- can be at membrane surface or intracellular
- binding > signalling cascade > transcription factor (NF-kB) > protein production to respond > cytokines
Dendritic cells?
- apc
- migrate to lymph nodes to activate lymphocytes
- link innate and adaptive
Role of antibodies?
- neutralization - binds toxin, viruses
- opsonization
- complement activation via classical pathway
- activate other cells
- RECOGNIZE specific epitopes not just patterns of antigen protein
How is tolerance obtained?
- delete autoreactive T cells in thymus
- delete autoreactive B cells in bone marrow
- anergy of autoreactive cells after development
- Tregs suppressing fnc
- immunoinhibitory receptors
- presence of barriers for priveleged sites
List components of INNATE immune system:
- physical barriers: skin, pH, mucus
- mast cells
- neutrophils
- macrophages
- NK cells
- dendritic cells
-non specific recognition (patterns); killing; signals for inflame; activation of adpative immune cells; no memory
How does innate system recog pathogen?
- TLR recognizing PAMP
2. inflammasome: cytoplasmic proteins send danger signal in presence of PAMPS > IL1 secretion to initiate inflamm
linking bt innate and adaptive
Dendritic cells
cytokines (from macrophages)
complement cascade
What are the chemical (non cellular) components of immune system?
4 C's: Cytokines Complements Chemokines Coagulation
What is phagocytosis? Who does it?
-recognition: TLR, Fc, mannose, complement
-pseudopod to surround pathogen
-engulf
-phagolysosomal fusion > digestion
» also lead to antigen presentation, and cytokine release
-neutrophils, macro, B cells, dendritic cells
How does immune system kill?
- Phagocytosis
- complement cascade
- ADCC: antibody-dependent cell mediated cytotoxicity
- ab opsonize for NK cells, neutrophils, eosinophils to relesase granules for killin - Defensins: antimicrobial from neutrophils
- Pentraxins; link pathogen adn phagocyte
Purpose of complements?
which one is important?
- direct killing (MAC) - C5b onward
- opsonization -C3b
- recruiting inflammatory cells -C3a, C5a
Role of cytokines?
ex:
-activate other cells
-chemotaxis
-activate liver to secrete proteins: complements, opsonization
-on bone marrow to recruit neutrophils
-on hypothalamus, fat, muscle > fever
-on dendtritic cells >migration and link adaptive response
IL1, IL6, IL12, TNFalpha
Why is C3 impt?
activation of complement > C3 convertase metabolizing C3 > C3a: ENDO PERM, activation of phagocytes = inflammation
>C3b (bigger piece): opsonization with receptor for phagocytes
def: recurrent infections
Early vs late complement cascade?
what if deficiency?
early: binds antigen-ab complexes > C3 activation def > not so serious b.c of multiple pathways to C3 C4 def in SLE
late: killing via MAC (creates holes in membrane) def > serious inf (gonorrhea, meningitis)
Describe B cell development
develops in bone marrow:
>ProBcell: commits to B cell line
>preBcell receptor: heavy chain gene rearrangement. checks for functional heavey chain else apoptosis.
>light chain gene rearrangement
>Bcell receptor. checks for functional else.
=Immature B cell with IgM expression
>exposed to self-antigen. Only those that DO NOT self-recog can leave bone marrow
Home via chemokines in blood > activated when in contact with antigen > diff, proliferate, mature:
IL10 >plasma cells > goes to bone marrow > produce antibodies > IgM first then others
IL4 > Memory B cells > IgG early response next time
Antibody structure, production, response
- Fc-constant for binding to receptors on phagocytes
- Fab-variable for recognition of antigen
- antibodies: opsonize, neutralize, activate complements, activate cells
Antibody isotypes and fncs
IgG: in serum, tissue, cross placenta. small. opson & complement activation
IgA: dimeric. in secretions (tracts!). Neutralization - bind and excrete. Week ops and activation.
IgM: first response. pentameric. big so not diffused well. in circulation. CANNOT recruit other cells. activate complements
IgE: trace amounts in serum. bound to mast cells under skin/mucosa > reactions to expel pathogen.
-allergies, parasites
IgD - didn’t mention
B cell tolerance
Central:
- immature B cell exposed to self-antigen. If recognize self > negative signal for apoptosis = NEGATIVE SELECTION
- TOLERANT B cells can leave bone marrow
Clonal selection hypothesis?
-common precursor cell > remove self-reactive immature lymphocytes > antigen presence would activate proliferation of specific lymphocyte differentiation
Describe B cell genetic Recombination
*must generate large repertoire of antibodies, but each must only recognize one specific antigen. < done via GENETIC RECOMBINATION > diveristy!
Bone Marrow:
-3 gene segments on antibody VARIABLE region rearranged and assembled:
-heavy chain: random V, then random D+J added to V
-light chain: kappa then lambda
-Heavy and light chain combination
*antigen independent
Lymph node: under specific signals
-isotype switching - recombination of CONSTANT genes
Describe B cell activation in lymph nodes.
1ary vs 1ary focus?
- goes to lymph node vis HEV
- surface antibody-antigen binding + coreceptor binding
- also helped by Thelper cells that recogn same antigen> express CD40L to CD4 on B cell + cytokine binding
- PRIMARY FOCUS: clonal expansion adn IgM in medullary cords
- 2ary FOCUS: B cell move to cortical area > germinal center > later better response. Needs presence of Thelper cell, follicular dendritic cells, activated B cells
What occurs in a germinal centre?
-activated B cells under strong cytokine signalling and interaction with dendritic cell, antigen, Thelper > rapid proliferation
-SOMATIC HYPERMUTATION occurs > B cells with higher affinity for antigen selected for = AFFINITY MATURATION
-ISOTYPE SWITCHING: recombination of CONSTANT genes expressed for same V region
»swollen lymph nodes. 1 wk post infection
T cell development
-Precursor formed in bone marrow
> arrive thymus: VJ rearrganement of TCR + positive selection + negative selection:
-Rearrange B chain - DJ then VDJ. CHECK PreT cells
-proliferate as DOUBLE NEGATIVE PreTcell. CHECK
-DOUBLE POSITIVE Immature T cell
-Rearrage alpha chain - VJ. CHECK. Now DOUBLE POSITIVE mature T cell (have both CD4 and CD8 receptors)
-positive selection- keep those that can recog self MHC and only express one CD coreceptor
-negative selection-rid those that can recog self antigen
- mature, self-restricted, self-tolerant, single positive NAIVE Ts migrate to 2ry lymphoid
- becomes effector cells after antigen exposure > proliferation and differentiation
CD4T vs CD8 T?
binds which MHC
*a:B TCRs
CD4
-help other cells; extracellular pathogens
-binds MHC 2
CD8
- kill cells with virus/intracellular pathogens
- binds MHC1
T cell tolerance
- Positive selection - can T cell bind self MHC? Yes - keep.
- Negative selection - can T cell bind MHC with self antigen? Yes - RID!
- test in medulla of thymus with APCs presenting peptides made by apcs, from macrophages, from extracellular fluid, and peptides of things outside thymus transcribed by AIRE gene
- priveleged sites
- Peripheral tolerance mechanisms:
- Treg suppression of naive autoreactive cells (natural in thymus; inducible in periphery); foxp3 transcription factor
- anergy of autoreactive cells
Immunological memory?
-2ry immune response
-B cells, T cells, antibodies of previous infection remain
>faster, stronger response next time
-long lived cells maintained by cytokines
What is B-T cognate interaction?
-antigen recogn > induce expression of CD40L and cytokines from Th2 cells > activate B cells
What is MHC?
What is MHC Restriction?
How is MHC diversity achieved?
- major histocompatibility complex
- antigen protein needs to be fragmented and specific epitope presented on MHC for TCR to recognize
- can bind many different aa sequences (motif)
- T cell is specific to that antigen on that MHC
- no recombination
- diveristy is inherited from each parent
MHC 1 vs 2? which cells have which?
binds to which T cells?
MHC I: on all nucleated cells
-binds CD8T for intracellular infections
MHC II: on apcs
-binds CD4T for extracellular infections
How are antigens presented?
-APCs take up: endocytosis or comes in
-degrade: phagolysosomes or proteasomes
-proteins unfolded adn cut
-specific peptide bind to MHC adn brought to surface
MHC II: produced and fuse with vesicle containing antigen while MHC I: have peptides brought to ER and packaged together
-T cell comes by and bind…
How are T cells activated?
-from APCs: dendritic cells, macrophages, B cell
1. TCR bind MHC with specific antigen
2. Co-stimulation: CD28 with CD80 (B7) ligand on APC
»gene transcription > cytokines > effects on other immune cells
ex: IL2 > further proliferation of T cells
> > effector T cells don’t need costimulation to respond!
What is anergy? How?
- T cell can’t be activated
- MHC and antigen signal but NO costimulation
- helps to prevent activation to self-antigen
Type of CD4 Helper T cells?
which cytokines are impt?
Naive CD4 T cells can differentiate to diff effectors under diff cytokines:
- Th1 - activate macrophage (IFN-gamma)
- Th2 - activate B cells (IL4, IL5)
- Tfh - activate B cells to form germinal centre (IL21, IL4)
- Th17 - enhance neutrophil response where Th1 and Th2 not enough; autoimmune. (IL17, IL6)
- Treg - suppressor T (TGF-beta, IL10)
How does TB hide from immune system?
- hides from lysosomal degradation > can’t be presented by MHCII
- does not enter cytoplasm > can’t be proteasased > can’t be presented by MHCI
- T cells can’t recognize.
- T cells surround the APCs with TB = granuloma
How does leprosy present differentially depending on host response?
cytokine levels > certain cell differentiation
- bias toward Th1 response > cell mediated presentation: macrophages can suppress > slow > damage to skin and nerves
- bias toward th2 > antibodies can’t access bacteria in macrophages > bacteria grow > severe destruction!
