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371 Cards in this Set
- Front
- Back
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humoral response ~~
(2) |
B cells => plasma cells,
AB release |
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R-naught =
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bDC
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b =
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efficiency of transmission
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D =
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duration of infectiousness
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C =
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# of people exposed
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R-naught > 1 =
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epidemic
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2 primary lymphoid tissues:
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1. bone marrow
2. thymus |
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all immune cells/precursors are made in the:
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bone marrow
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what is the thymus for?
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T cell precursors mature here
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immune cell precursors travel to:
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secondary lymphoid tissue
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4 types of secondary lymphoid tissue:
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1. spleen
2. lymph nodes 3. tonsils 4. Peyer's Patches in SI |
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stem cells proper create:
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more stem cells
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pluripotent stem cells create:
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every kind of cell except for more stem cells
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hemapoietic stem cells give rise to ALL:
(3) |
1. lymphoid
2. myeloid 3. erythroid cells |
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innate immunity =
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first line of defense
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5 cells/mlcls of innate immunity:
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1. granulocytes
2. NK's 3. macrophages 4. dendritic cells 5. mlcls like complement, cytokine |
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adaptive immunity =
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2nd line of defense
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3 cells/mlcls of adaptive immunity:
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1. B cells (which become plasma cells)
2. T cells 3. AB's, cytokines |
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chemokines are small peptides released by:
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an infected cell
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what do chemokines do?
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migrate to immune cells, attach, and activate them to travel to infected cell, tracking along chemokine migration
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cytokines participate in:
(3) |
auto, para, and endocrine signalling
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4 types of pathogen:
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1. bacteria
2. viruses 3. fungi 4. parasites |
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2 types of parasites:
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1. protozoa
2. worms |
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basic immune response: bacteria enter through cut =>
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dendritic cells take up bacterial antigen => enter lymphatic system => enter lymph nodes => B and T cells travel to site of infection
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B cells ~~ surface immunoglobins that:
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recognize antigens
=> become AB's when they detach |
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for the most part, B and T cells will express only ONE:
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type of antigen-recognizing receptor
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clonal expansion: progenitor cells =>
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many different, specific lymphocytes
- specific pathogen hits => activated lymphocyte proliferates |
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"multivalent" =
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having >1 epitope
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epitope =
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part of an antigen to which an AB attaches
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some multivalent antigens have different:
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epitopes (different AB's attach)
some have all the same in both cases, multiple AB's will attach |
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with secondary response onward, AB amount and affinity:
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increase
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innate response:
(5) |
1. rapid (hours)
2. fixed recognition 3. general 4. recognition is constant during response 5. no memory of old infections |
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adaptive immune response:
(4) |
1. slow response (days to weeks)
2. very specific 3. recognition improves over the life of the infection 4. memory of old infections remains in the form of specific B and T cells |
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3 types of lymphocytes:
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1. NK's
2. T cells 3. B cells |
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NK's:
(2) |
1. destroy antigenic cells
2. large, look like marcophages |
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3 kinds of T cells:
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T cytotoxic
T helper T memory |
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difference between T cytotoxic and T helper cells:
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T cytotoxic cells *destroy* antigenic cells; helper cells help Innate Immune cells to destroy
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2 kinds of B cells:
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1. plasma cells, which release AB's
2. B memory cells |
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4 locations of lymphocytes:
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1. blood
2. lymph 3. immune tissues 4. immune organs |
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histologically, B and T cells look:
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exactly alike
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plasma cell nucleus =
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yoshi egg off to the side
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where in plasma cells are AB's synthesized?
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cytoplasm
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3 locations of plasma cells:
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1. lymph
2. imm. tissues 3. imm. organs |
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the process of B cell mitosis and differentiation forms:
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nodules/follicles of B lymphocytes
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the light interior of a developed follicle is called the:
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germinal center
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what 2 kinds of cells are found in the germinal center?
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1. immunoblasts
2. B memory cells |
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immunoblast =
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precursor to plasma cell
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a B cell follicle is called a primary follicle if it does NOT have:
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a germinal center
=> it's NOT producing immunoblasts/B memory cells |
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**a germinal center indicates**:
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B cells responding to an antigen with clonal proliferation and differentiation
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both macrophages and dendritic cells:
(4) |
1. come from bone marrow stem cells
2. present antigen and phagocytose 3. are found in lymph, imm. tissues, and imm. organs (**not in blood**) 4. are LARGE, with large nucleus |
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follicular dendritic cells:
(3) |
1. present antigens
2. **located only in the lymph nodes** 3. large with large nucleus |
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immune tissues =
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UNencapsulated clusters of immune cells
- only around when needed |
|
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cells of immune tissues are either:
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reacting to antigen or actively patrolling for antigen
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immune tissues are located at sites of:
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constant antigen exposure
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2 sites of constant antigen exposure:
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1. skin
2. mucosa |
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mucosa =
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lining of openings to environment
|
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immune tissues are also called:
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MALT
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MALT =
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mucosa-associated lymphoid tissues
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2 prominent kinds of MALT:
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1. GALT
2. BALT |
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GALT =
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GI-associated
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GALT are found in:
(2) |
1. lam propria of SI (including Peyer's patches)
2. tonsils/adenoids |
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Peyer's Patches =
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dense clusters of immune cells
|
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adenoids =
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tonsils of the nose
|
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the pharynx has ______ which are lined with immune cells
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crypts;
food and stuff fall in them and are checked out by those imm. cells |
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BALT =
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bronchus-associated
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immune organs =
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ENCAPSULATED aggregates of immune tissue
(that is, surrounded by CT) |
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3 types of imm. organs:
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1. thymus
2. lymph nodes 3. spleen |
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the thymus comes from:
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the 3rd pharyngeal pouch
|
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thymus is the site of:
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thymocyte maturation
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thymocyte =
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T cell precursor
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thymus is large in:
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children/teens,
atrophies in adulthood |
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the thymus is divided into:
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lobules
|
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each thymus lobule has 2 layers:
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cortex and medulla
|
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cortex of thymus lobule =
|
densely-aggregated thymocytes, epithelial cells, and macrophages
|
|
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medulla of thymus lobule =
|
loosely-aggregated thymocytes, epithelial cells, macrophages, and Hassels corpuscles
|
|
|
Hasel's corpuscles =
|
whorls of keratinized epithelial cells
|
|
|
what do the epithelial cells of the thymus do?
(3) |
1. form blood-thymus barrier
2. form the stroma 3. aid T cell maturation |
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stroma =
|
supporting framework
|
|
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T cells arrive at thymus via circulation =>
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(called thymocytes) => pass from cortex to medulla and mature into T helper or T cytotoxic cells => exit back into circulation
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lymph nodes:
(3) |
1. full of T and B cells
2. filter lymph for antigens 3. sites of APC's |
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3 regions of a lymph node:
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1. cortex
2. paracortex 3. medulla |
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3 cells of the lymph node cortex:
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1. B cells
2. follicular dendritic cells 3. macrophages |
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2 cells of the lymph node paracortex:
|
1. T cells
2. dendritic cells |
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1 type of cell of the lymph node medulla:
|
plasma cells in cords
|
|
|
all lymph sinuses contain:
(2) |
1. lymph
2. macrophages |
|
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**paracortex of lymph nodes contains:**
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high endothelial venules
|
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significance of high endothelial venules:
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T and B cells arrive at lymph nodes via these blood vessels
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two kinds of tissue at the spleen:
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1. white pulp
2. red pulp |
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what does white pulp do?
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filters blood for antigens
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3 layers of white pulp:
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1. T lymphocyte-rich layer
2. mantle zone 3. marginal zone with sinuses |
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T lymphocyte-rich layer of white pulp:
(2) |
1. aka PALS
2. surrounds arteries/arterioles |
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mantle zone of white pulp:
(2) |
1. rich in B cells
2. when antigens are present, contains secondary follicles with germinal centers |
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marginal zone with sinuses:
(2) |
1. outermost layer of white pulp
2. forms the interfaces between white and red pulp |
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red pulp:
(3) |
1. non-immune portion of spleen
2. removes old/damaged RBC's 3. contains LOTS of macrophages |
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the red pulp consists of:
(3) |
1. capillaries, which empty into cords and venous sinusoids
2. cords, where macrophages pick through RBC's 3. venous sinusoids, where blood leaves spleen |
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venous sinusoids of the spleen are:
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fenestrated/discontinuous
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basic pathway: pathogen =>
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II => AI via APC's
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3 kinds of APC's:
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1. macrophages
2. dendritic cells 3. B cells |
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***which innate imm. cells are found in tissues?***
(3) |
1. macrophages
2. dc's 3. mast cells |
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***which innate imm. cells are found circulating in the blood?***
(2) |
1. all granulocytes
2. NK's |
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which InnImm cells kill bacteria?
(4) |
1. Complement
2. neutrophils 3. macrophages 4. dc's |
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which InnImm cells kill parasites?
(1) |
eosinophils
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which InnImm cells kill fungi?
(1) |
neutrophils
|
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which InnImm cells kill viruses?
(5) |
1. Complement
2. interferons 3. NK's 4. dc's 5. macrophages |
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what are the granulocytes?
(3) |
neutrophils, eosinophils, and basophils
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neutrophils:
(4) |
1. aka PMN's
2. **most prevalent WBC** 3. segmented nucleus = mature 4. lots of granules |
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neutrophils are best at:
|
phagocytosing bacteria and fungi
- lots of different receptors help them recognize lots of different bacteria |
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**neutrophils undergo __________ once they've ingested bacteria**
|
apoptosis
- macrophages clean up the resulting debris |
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a bad infection => LOTS of:
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IMMATURE neutrophils at site of infection
|
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extravasation =
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process of circulating neutrophil attaching to endothelium and entering tissue
|
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4 stages of extravasation:
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1. rolling adhesion
2. tight binding 3. diapedes 4. migration to specific part of the tissue |
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diapedes =
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neutrophil sliding in from blood vessel into tissue
|
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some patients have a defect in:
|
diapedes
|
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neutrophils have 2 forms of phagocytosis:
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O2-independent,
O2-dependent |
|
|
O2-dependent phagocytosis uses:
|
ROS intermediates to destroy bacterial membranes and DNA
|
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defects in the phagocytotic process =>
|
persistent bacterial infection
|
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eosinophils are great at killing:
|
parasites
|
|
|
process of eosionophil killing:
(3) |
1. IgE binds parasite
2. Fc receptors on eosinophils attach to IgE 3. eosinophils release granules into parasite |
|
|
basophils ~~
(2) |
allergies and inflammation
|
|
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basophils' Fc receptors have:
|
a high affinity for IgE
|
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mast cells come in two flavors:
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mucosal and connective
|
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mast cells cause:
|
inflammation
|
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|
mast cells release:
(2) |
histamine and leukotrienes
=> vasodilation, inc. permeability, and immediate hypersensitivity |
|
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mast cells are implicated in:
(2) |
1. asthma
2. anaphylaxis |
|
|
anaphylaxis =
|
allergic rxn
|
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NK's are:
|
early line of defense against viral infections
- act before CD8+ T cells get there |
|
|
NK's:
(2) |
1. large and granular
2. part of II |
|
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what do NK's do?
|
secrete IFN-y and destroy infected/stressed cells
|
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NK's are activated by:
(4) |
1. IL-R
2. TNF-alpha (both produced by macrophages) 3. IFN-a 4. IFN-Beta (both produced by virus-infected cells) |
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NK's express inhibitory receptors and healthy cells express:
|
HLA;
HLA binds to inhibitory receptors, keeping NK from destroying healthy cell |
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***tumor/infected cell does NOT express:***
|
HLA
=> NK's activated, kill cell |
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***tumor cells DO express:***
|
MIC
=> recognized as kill target by NK's |
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two types of NK activation:
|
1, MIC-mediated
2. AB-mediated |
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AB-mediated activation of NK's is a:
|
late-stage mechanism
- NK's recognize coat of AB's around virus-infected cell |
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macrophages are long-
|
lasting
|
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macrophages recognize pathogens via:
(3) |
1. toll-like receptors
2. Fc r's 3. Complement r's |
|
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what can macrophages do?
(2) |
both present antigens AND phagocytose
|
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Fc r's are used during:
|
late stage of infection
|
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PAMP =
|
class of mlcls found on surface of pathogens
|
|
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macrophages cause inflammation by:
|
secreting cytokines, which recruit OTHER immune cells
(e.g. IL-6) |
|
|
macrophages are first:
|
responders
- constantly roving |
|
|
septic shock =
|
massive macrophage response to infection
=> severe inc. in blood vessel permeability => strong dec. in BP and collapse of blood vessels => organ failure |
|
|
3 types of dc's:
|
1. conventional
2. follicular 3. plasmacytoid |
|
|
conventional dc's:
(2) |
1. found within T cell-rich areas
2. prime naive T cells coming from thymus by presenting antigens |
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follicular dc's:
(2) |
1. found within B cell-rich areas
2. hold antigens for years => long-term memory |
|
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plasmacytoid dc's:
(2) |
1. secrete type I IFN's
2. aid activation of NK's |
|
|
compromised Innate Immune response =>
|
uncontrolled infection
|
|
|
after being presented with antigen in the lymph, T anc B cells:
|
TRAVEL to infection site
|
|
|
Complement:
(3) |
1. part of II
2. a series of proteins that act immediately 3. circulate in the blood |
|
|
Complement functions as:
(2) |
1. opsonins
2. anaphylatoxins |
|
|
opsonin =
|
s/t that binds a foreign substance to flag it for phagocytosis
|
|
|
anaphylatoxin =
|
chemoattractant that recruits leukocytes and aids in inflammation/vascular permeability
|
|
|
Complement is activated via 3 pathways:
|
1. alternative
2. classical 3. leptin pathway |
|
|
alternative pathway:
(2) |
1. major pathway
2. C3b-mediated |
|
|
early part of alternate pathway generates:
|
C3b fragment, which then binds to microbe
=> phagocytosis |
|
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after binding to microbe => series of steps =>
|
formation of MAC => pores in microbe
(late-stage) |
|
|
MAC =
|
membrane attack complex
|
|
|
classical pathway:
(2) |
1. AB-mediated
2. AB's attract C1 to microbe => MAC |
|
|
lectin pathway: mannoses on surface of microbe =>
|
mannose-binding lectin (MBL) => signal for MAC => microbe death
|
|
|
Complement action can be inhibited, to:
|
keep good cells safe
|
|
|
in early alternative pathway, 3 factors keep C3b complex from forming:
|
1. DAF
2. MCP 3. factor I |
|
|
in late alternative pathway, ________ prevents MAC from forming
|
CD59
|
|
|
deficient in Complement =>
|
immune deficiencies
|
|
|
***MHC =
|
linked set of genes on chromosome 6 that result in a complex of mlcls
|
|
|
2 classes of MHC:
|
Class 1 (HLA-A, B, and C)
Class 2 (HLA-DP, DQ, DR) |
|
|
HLA =
|
human MHC
|
|
|
HLA stands for:
|
human leukocyte antigen
|
|
|
***MHC functions:***
(3) |
1. peptide antigen presentation to T cells
2. T cell education 3. T cell activation |
|
|
necessary protein associated with MHC =
|
Beta-2 microglobulin
(on chromosome 15) |
|
|
Class 1 HLA:
(4) |
1. a total of 6 different mlcls (3 from mom, 3 from dad)
2. ALL 6 are expressed by a cell 3. ***expressed in all somatic cells*** 4. binds to *endogenous* antigens |
|
|
endogenous antigens are antigens found:
|
within the cell
e.g. viral infection |
|
|
***major function of Class 1 HLA =
|
present endogenous peptides to CD8+ T cells
=> tells T cell that host is infected => activated T cell kills it |
|
|
class 1 HLA mlcls are absolutely necessary for:
|
CD8+ T cell recognition and activation
|
|
|
***a T cell can recognize an antigen ONLY IF:***
|
that antigen is bound to MHC
|
|
|
HLA Class II are expressed as a total of ____ different proteins:
|
14;
6 different alpha-chains, 8 different Beta-chains |
|
|
Class II HLA's bind:
|
exogenous antigens
- present them to **CD4+** (helper) T cells |
|
|
***Class II HLA's are expressed ONLY IN:***
(2) |
1. APC's
2. thymus epithelial cells |
|
|
when presented with antigen, both CD4+ and CD8+ T cells attach to:
(2) |
MHC and antigen peptide
=> trimolecular complex |
|
|
inflammation =
(2) |
increased blood flow and WBC's
|
|
|
***ANY cell with MHC CLass I can present to:***
|
CD8+ T cells
(any cell with Class II can present to CD4) |
|
|
**defect in MHC genes/mlcls =>
|
compromised immune response to bacteria and viruses
|
|
|
MHC also ~~
(4) |
1. allergies
2. autoimmunity 3. organ transplants 4. tumor rejection |
|
|
no innate immunity =>
|
death
|
|
|
B cells recognize ___________ antigens
|
**whole**
|
|
|
T cells can recognize ONLY:
|
*peptides*,
and ONLY in the context of MHC |
|
|
APC's ~~ innate immunity mechanism to:
|
activate adaptive immunity
|
|
|
**APC's REQUIRE expression of:**
|
MHC
(Class I, II, or both) |
|
|
4 steps to presenting an antigen to T cells:
|
1. take up antigen
2. degrade it into peptides 3. load peptides onto MHC 4. present MHC-peptide complex to specific T cell |
|
|
what's the best APC?
|
dendritic cell
|
|
|
immature dc's are:
|
phagocytotic
- mature ones are APC's |
|
|
what are the 2 antigen-presenting pathways?
|
endogenous and exogenous
- both use the 4 general steps |
|
|
typical case of using endogenous pathway =
|
viral infection
|
|
|
endogenous pathway: virus makes proteins =>
|
cell breaks down proteins in the cytoplasm => synthesis of MHC Class I => **TAP** delivers peptide to MHC Class I
|
|
|
viruses will try to inhibit:
|
various points of the endogenous pathway
|
|
|
the exogenous pathway is initiated by:
|
endocytosis of foreign substance
(usually bacterial or fungal) |
|
|
exogenous pathway: B cells endocytose antigen bound to surface Ig OR macrophages' Fc r's bind AB-antigen complex =>
|
antigens are placed into phagolysosomes => degraded by pH, proteosomes => AB's recycled => MHC Class II mclcls bound with CLIP are in the phagolysosomes => CLIP is removed, MHC attaches to peptide => moves to surface => presentation to CD4+ T cell
|
|
|
***APC's express BOTH Class I AND Class II mlcls =>
|
both pathways can be used simultaneously by APC's
|
|
|
***MHC restriction*** =
|
T cells are trained to activate ONLY when presented with a specific antigen and a specific MHC complex
- if one of those two is different, that T cell will NOT bind/activate |
|
|
T cell education =
|
MHC restriction
|
|
|
superantigens ~
|
NO MHC restriction
|
|
|
superantigens =>
|
enourmous, non-specific T cell/immune response
(think about what happens when both kinds of T cells go rampant) |
|
|
some bacterial and viral components are:
|
superantigens
|
|
|
MHC Class I and Class II are highly:
|
polymorphic
- there is a HUGE difference between the MHC's of one individual from those of another |
|
|
MHC polymorphism influences:
|
the repertoire of antigens that an individual's T cells will recognize
(and also presents a major transplant barrier) |
|
|
deficiencies in MHC mlcls =>
|
much greater rates of infection
|
|
|
2 other Class I HLA's:
|
HLA-G,
HLA-E |
|
|
what does HLA-G do?
|
protects fetus from maternal immune system
|
|
|
what does HLA-E do?
|
serves as a ligand to NK cell receptors
|
|
|
codominant inheritance of MHC genes =
|
each MHC gene that's inherited is expressed *equally*
- there's no such thing as expressing dad's MHC genes more |
|
|
close linkage of MHC genes =
|
MHC genes are inherited as ONE UNIT from each parent
|
|
|
advantages of MHC heterozygosity: more heterozygous =
|
greater rebuff of infections
|
|
|
B cells will always take up and break down an antigen, in order to:
|
present it to T cells
|
|
|
B cells CANNOT release AB's until:
|
they are plasma cells
(which follows T cell interaction) |
|
|
5 classes of AB's:
|
IgM, IgG, IgD, IgE, and IgA
|
|
|
both light and heavy chains of AB's have:
(2) |
a Constant region and a Variable region
|
|
|
V, D, and J =
|
gene segments for heavy chains
|
|
|
Vk, Jk, V-lambda and J-lambda encode:
|
variable region of light chains
|
|
|
variable region rearrangement:
|
V's and J's of light chain are spliced together, as are VDJ segments of heavy chain DNA
|
|
|
in heavy chain variable region gene rearrangement, D and J:
|
are joined first, then V is spliced to DJ
|
|
|
greater variety: VDJ's and V/J's are spliced at:
|
different points of their segments
|
|
|
still greater variety of AB: an enzyme adds a random amount of:
|
nucleotides between V and D and D and J
(heavy chain only) |
|
|
once VDJ regions are joined,
|
no further nucleotides can be added
|
|
|
nucleotides added are called:
|
N regions
|
|
|
heavy chain only: 2/3's of all VDJ rearrangements are:
|
**non-productive**
|
|
|
what does it mean for a rearrangement to be non-productive?
|
rearrangement produces a *frame shift* such that a **functional heavy chain cannot be expressed**
|
|
|
***if a rearrangement on the first allele of an AB gene is productive, what happens to the second allele?
|
it does NOT undergo rearrangement
- it's deactivated |
|
|
***if the rearrangement on the first allele of an AB gene is NON-productive, what happens at the second allele?
|
**it undergoes rearrangement**
|
|
|
another component of AB diversity =
|
different combinations of light and heavy chains
|
|
|
B cells complete differentiation in the:
|
spleen
- then accumulate in the blood, lymph nodes, etc. |
|
|
immature B cells express only:
|
IgM
|
|
|
B cells of the marginal zone of the follical express both:
|
IgM AND IgD
|
|
|
significance of expressing both IgM AND IgD =
|
check
|
|
|
germinal centers = sites of:
|
B and T cell interactions
|
|
|
what 2 important processes occur in B cells in the germinal centers?
|
1. switch recombination (heavy chain only)
2. somatic hypermutation (both chains) (both occur after antigen has been bound) |
|
|
heavy chain class switch =
|
enzymes bring switch sites together =>
Variable region genes are expressed with C regions of other classes (***the variability is in changing C regions, not V regions***) |
|
|
significance of heavy chain switch recombination =
|
a greater variety of AB's, since they cause a different combination of V and C regions
|
|
|
***somatic hypermutation = ***
|
POINT mutation that alters a sequence
(ONLY a base substitution - not deletion or insertion) |
|
|
somatic hypermutations:
(3) |
1. occur ONLY once VDJ or V/L have been rearranged
2. mostly random, but there are certain hotspots on an AB gene 3. occurs with every cell division - very frequent |
|
|
consequences of somatic hypermutation:
(3) |
1. silent mutation
2. lethal mutation (B cell eventually dies because it's useless) 3. AA replacement mutation |
|
|
an AA replacement mutation has three possible outcomes:
|
1. neutral - no effect on antigen binding
2. deleterious - decreases antigen binding => B cell eventually apoptoses 3. advantageous - improves antigen binding by AB or gives B cell an advantage in clonal expansion |
|
|
B cells are made in the:
|
bone marrow
|
|
|
B cells complete their maturation/differentiation in the:
|
spleen
|
|
|
mature B cells express 2 different classes of Ig:
|
IgM, IgD
|
|
|
3 subsets of mature B cells:
|
1. follicular
2. Marginal Zone B cells 3. B-1 |
|
|
the majority of mature B cells are:
|
follicular B cells
(it's the default pathway) |
|
|
follicular B cells:
(4) |
1. naive
2. T-cell dependent 3. respond slowly to antigen 4. short-lived (3 months) |
|
|
"naive" means the immune cell has never:
|
seen an antigen before
|
|
|
"T-cell dependent" =
|
**requires** T-cell help
|
|
|
follicular B cells ultimately end up as:
|
**long-lived** plasma and memory cells
|
|
|
MZ and B-1 cells share characteristics:
(6) |
1. NOT naive
2. long-lived 3. self-renewing (will make copies of themselves) 4. ~ T-INdependent immune response 5. respond quickly to antigen 6. first line of protection against pathogen |
|
|
B-1 cells reside in:
|
the periphery
|
|
|
B-1 cells make plasma cells that stalk the:
|
lamina propria of the gut
|
|
|
MZ cells reside in:
|
the marginal zone of a follicle in the spleen
|
|
|
MZ cells make plasma cells that stay in:
|
the spleen
|
|
|
MZ and B-1 cells *become* such when:
|
their BCR's are bound to an antigen
|
|
|
clonal selection =
|
only B cells specific to a particular antigen are activated
|
|
|
antigen binds naive FO cells' BCR =>
|
cell proliferates, differentiates, and activates (with help of T cells) => plasma cells and memory cells
|
|
|
memory cells become plasma cells _____ ________ than original B cells
|
**more quickly**
- magnitude of B cell response is also MUCH greater via memory cells |
|
|
first response ~
|
IgM-type AB's
|
|
|
second response ~
|
IgG type AB's
|
|
|
antigens are classified into 2 broad categories:
|
1. T-independent
2. T-dependent |
|
|
"T-independent" antigen means:
|
the antigen activates B cells without help of T cells
|
|
|
2 types of T-independent antigens:
|
T1 and T2
|
|
|
T1 (independent) antigens ~
|
nonspecific, general activation of B cells
- weak |
|
|
T2 (independent) antigens:
(3) |
1. predominantly bound by IgM
2. activate B cells via cross-link of *multiple* BCR's 3. requires antigen to have repeating epitopes to do so |
|
|
T2 antigens can ONLY generate a:
|
**primary immune response**
- they will *never* cause the creation of B memory cells |
|
|
T-dependent antigens activate B cells only with:
|
help of T cells
(antigen-bound signal is too weak to activate B cell on its own) |
|
|
T-dependent antigens:
(3) |
1. globular antigens - no repeating structure
2. predominantly bound by IgG 3. *do cause* secondary response => long-lived plasma and memory cells |
|
|
what happens when a TD antigen is sensed?
|
antigen binds B cell => internalized => attached to MHC Class II => presented to T cell => TCR binds to form trimolecular complex => **T cell increases production of CD40L => CD40L attaches to CD40 on B cell => B cell is activated => prolif/diff to plasma/memory cells
|
|
|
***both B and T cells require:***
|
**2** signals to cause B cell prolif/diff
|
|
|
activation: signal 1 for B cell =
|
BCR-antigen binding
|
|
|
activation: signal 1 for T cell =
|
TCR-MHC-antigen
|
|
|
activation: signal 2 for B cell =
|
CD40 bound to CD40L
|
|
|
activation: signal 2 for T cell =
|
B7 (receptor on B cell) bound to CD28 (from T cell)
|
|
|
***if there is no signal 1, ***
|
there is no signal 2 ==> activation does not occur
|
|
|
specificity of the immune response: **only the B and T cell that are interacting with that specific antigen will receive:**
|
signal 2 and thus proceed to activation
- no other B or T cell will receive a signal 2 |
|
|
**T cells are already activated by:
|
dc's before they interact with B cells
|
|
|
what do dc's make T cells do?
|
up-regulate CD40L before they come to B cells
|
|
|
B and T cells need a _________ signal for the immune response to produce plasma/memory cells
|
**constant**
- a single signal is insufficient to make the process go all the way through |
|
|
**2 things that cytokines released by T cells do:**
|
1. aid in recognition b/w B cells and T cells
2. control H chain switching |
|
|
**germinal centers are composed of:**
|
follicular dc's, T cells, and B cells (light zone) +
*activated* B cells that are prolif/differentiating (dark zone) |
|
|
follicular dc's present antigen to B cells via:
|
icosomes,
which are then taken up by B cells => interaction with T cells |
|
|
dark zone of germinal center =
|
**rapidly-dividing* B cells that don't have time to express BCR's
|
|
|
somatic hypermutation occurs at:
|
check
|
|
|
following somatic hypermutation, those centrocytes that improve their ability to recognize/bind antigen survie;
|
those that don't, die
|
|
|
B cell tolerance =
|
keeping B cells from acting against good/healthy cells
- **b/c of the randomness, it's inevitable that some B cells will recognize self-antigens** |
|
|
4 mechanisms of B cell tolerance:
|
1. central deletion
2. receptor editing 3. peripheral deletion 4. anergy |
|
|
central deletion =
|
autoreactive B cells are eliminated in the bone marrow as soon as they express BCR
|
|
|
receptor editing =
|
B cells in bone marrow that have expressed a BCR and thus received the death signal have a short window to change the light chain of that BCR and thus avoid being autoreactive
|
|
|
peripheral deletion =
|
transitional (centrosome and centrocyte) autoreactive B cells in the spleen are programmed to undergo apoptosis once they encounter an antigen
- mature cells do not have this program |
|
|
anergy refers to:
|
functionally silent B cells
- some autoreactive B cells dont receive a death signal, but their affinity for antigen is so low that chronic encounters with antigen => unable to become activated by antigen |
|
|
how do most transitional B cells die?
|
via peripheral deletion
|
|
|
how frequently are autoreactive are B cells made?
|
constantly
|
|
|
T cells ~~
(2) |
graft rejections and autoimmunity
|
|
|
what are CD4 and CD8?
|
receptors that assist TCR
|
|
|
which MHC class do CD4+ T cells associate with?
|
Class II
|
|
|
in both cases, the binding of MHC+peptide into trimolecular complex results in:
|
cytokine release
(for CD4+ cells, that leads to activating B cells; for CD8+, that leads to killing infected cell) |
|
|
**BOTH CD4+ and CD8+ cells can cause:
|
pro- OR anti-inflammatory responses
|
|
|
how do T cells recognize an antigen?
|
via TCR
(and only if the antigen is bound to an MHC mlcl) |
|
|
TCR's are similar to:
|
Ig's
- they recognize peptide epitopes (in context of MHC) |
|
|
in order for a TCR to bind a peptide effectively, it requires:
|
a specific MHC to be bound to that peptide
(aka MHC restriction) |
|
|
when is MHC restriction established? in other words, when does the T cell learn to recognize that specific MHC?
|
**during positive selection** in the thymus
(they start out naive, then they get educated to recognize only that MHC-antigen) |
|
|
general process of lymphocyte maturation:
(3) |
1. proliferation
2. expression of antigen receptor (TCR or BCR) 3. selection of *useful* antigen receptor |
|
|
thymocyte development occurs in discrete stages, distinguished by:
|
cell surface markers
|
|
|
progress of thymocyte maturation: stem cell =>
|
DN thymocyte => pre-TCR t => DP t => SP thymocyte
|
|
|
proliferation of T cells:
(3) |
1. antigen-independent
2. new thymocytes from bone marrow still lack TCR's 3. ~ DN t's |
|
|
what does it mean for a thymocyte to be DN?
|
it expresses *neither* CD4 nor CD8
|
|
|
TCR gene expression involves many random genetic events, which means it's:
|
inefficient
=> results in failure more often than not |
|
|
TCR genes, like Ig, have:
|
V, D, J, and C regions
recombination/splicing => ONE each of V, D, J, and C => TCR specificity |
|
|
further variation comes in the form of junctional diversity, which means:
|
removing/adding nucleotides from/to V, D, and J regions
most variable areas |
|
|
what's the most important process in determining variability?
|
juncitonal diversity
|
|
|
how many TCR's can there possibly be?
|
> 10^16
|
|
|
a DN t will become:
|
a pre-TCR thymocyte,
which expresses a rudimentary TCR |
|
|
pre-TCR's signal their thymocytes to:
(3) |
1. stop further rearrangement of TCR gene
2. induce proliferation 3. up-regulate the expression of CD4 AND CD8 at the same time |
|
|
once pre-TCR thymocytes have expressed both CD4 and CD8 r's, they are called:
|
DP t's,
which have functional TCR's |
|
|
***thymocytes which fail to express a functional TCR undergo:***
|
apoptosis
- this occurs to 98% of the thymocytes that you start out with |
|
|
after becoming DP t's, thymocytes go to the thymus for:
|
thymic education
|
|
|
thymic education =
|
being presented with antigen for the first time, so as to develop specificity or be killed
|
|
|
4 different responses to thymic education:
|
1. weak (low to moderate) recognition/affinity for MHC Class I + peptide
2....for *Class II* MHC + peptide 3. NO recognition for MHC+peptide 4. STRONG recognition/affinity of MHC+peptide |
|
|
positive selection =
|
how those DP t's that show weak recognition/affinity for MHC+peptide during thymic education receive signals for further development
|
|
|
what's the result of NO recognition of MHC+peptide?
|
apoptosis
|
|
|
negative selection =
|
how those DP t's that show *strong* affinity for MHC+peptide are **selected against** and apoptose
|
|
|
what's the reason for negative selection?
|
it protects against potential autoreactive cells
|
|
|
so: no (or too low) affinity AND strong affinity of DP t for MHC+peptide both =>
|
apoptosis
|
|
|
***after thymic selection, DP t's down-regulate:***
|
**either** CD4 *or* CD8
=> become SP t's |
|
|
**SP t's recognize peptides from foreign antigens presented by MHC cells, but do NOT recognize:
|
peptides from self-antigens
- if they do, if means you're autoimmune |
|
|
the SP t's leaving the thymus are:
|
**naive** T cells
(the thymocytes before this were NOT naive, but these T cells are) |
|
|
naive T cells (aka SP t's) circulate between:
|
the blood and the lymph nodes
|
|
|
upon presentation of an antigen via MHC, a naive T cell will:
|
activate/prolif/diff into a CD4+ or CD8+ T cell
(depending on which co-receptor it chooses to express) |
|
|
if naive T cells are not presented with an antigen, they:
|
die in about 6 weeks
|
|
|
how many signals do T cells need to fully activate?
|
2
|
|
|
what are the 2 signals that T cells need to be fully activated?
|
1. trimolecular complex
2. CD28 bound to B7 |
|
|
CD28 =
|
mlcl expressed by T cell
(called a "co-stimulatory" mlcl) |
|
|
B7 =
|
receptor expressed by APC's
|
|
|
***in absence of signal 2, T cells become:***
|
anergized
- no longer responsive to antigen stimulation |
|
|
which 2 mlcls help the T cell with adhesion to APC's?
|
LFA-1,
VLA-4 |
|
|
what does LFA-1 attach to?
|
ICAM 1
(on APC, in endothelium) |
|
|
what is CTLA-4?
(2) |
1. a mlcl expressed by naive T cell
2. *inhibits* signal transduction to T cell =. T cell doesn't get activated |
|
|
**even though it's bound in the tmc, the TCR's short cytoplasmic tail is insufficient to:
|
send signals down to the nucleus and activate the T cell
|
|
|
what's the solution to a TCR's short cytoplasmic tail?
|
4 different cd3 proteins associated with TCR
- their cytoplasmic tails containn ITAM regions that become phosphorylated once TCR forms tmc |
|
|
P'n of ITAM regions of cd3's =>
|
additional mlcls that cause a cascade to reach the nucleus and induce gene expression of the various components required for T cell activation/proliferation
|
|
|
induction of T cell proliferation is dependent on:
|
IL-2, a cytokine
|
|
|
IL-2 is initially released from:
|
an APC
|
|
|
after the initial IL-2 binds to the T cell, the T cell makes:
|
more IL-2,
which then acts in an autocrine fashion on the T cell |
|
|
burst of IL-2 to T cell =>
|
proliferation of **antigen-specific** T cell
(i.e. clonal expansion) |
|
|
you shouldn't have too many T cells; activated T cells are donw-regulated in two ways:
|
1. CTLA-4
2. AICD |
|
|
CTLA-4 prevents:
|
T cell from binding APC
|
|
|
AICD stands for:
|
activation-induced cell death
|
|
|
AIDA process: following activation, FaS Ligand is up-regulated; =>
|
since FaS (its receptor) is constitutively expressed on all T cells, activated T cells that come into contact with other activated T cells are made to apoptose
|
|
|
effector functions of T cells are gained in the:
|
peripheral tissues
|
|
|
"effector functions" of T cells =
(2) |
helper or cytotoxic functions
|
|
|
after activation/clonal expansion, T cells will diff. into:
(2) |
effector OR memory cells
|
|
|
memory cells:
(2) |
1. can last for 30+ years
2. critical for vaccines to be effective |
|
|
***CD4+ T cells become one of three different types:***
|
Th1
Th2 Th17 |
|
|
CD4+ Th1 cells:
(2) |
1. secrete pro-inflammatory cytokines like INF-g and TNF-a
2. recruit monocytes |
|
|
IFN-y:
(2) |
1. a pro-inflammatory cytokine
2. enhances macrophage and dc abilities (killing and presentation) |
|
|
CD4+ Th2 cells:
(4) |
1. secrete anti-inflammatory cytokines
2. promote B cell prolif. 3. recruit eosinophils 4. repair tissues |
|
|
what anti-inflammatory cytokines do Th2 cells release?
|
IL4 and IL5
|
|
|
Th1 and Th2 block each other from:
|
differentiating into other types
|
|
|
CD4+ Th17 cells:
(2) |
1. somewhere in between pro- and anti-inflammatory
2. recruit monocytes and neutrophils |
|
|
neutrophils clear:
(2) |
bacteria and fungi
|
|
|
what determines what a CD4+ cell will differentiate into?
(2) |
different cytokines and TF's
|
|
|
what do CD8+ cells differentiate into?
|
CTL's
(cytotoxic T lymphocytes) |
|
|
***CD8+'s become CTL's in 3 different ways:***
|
see below
|
|
|
first way to differentiate into CTL:
|
dc's express B7, activating T cell
=> T cell makes IL-2, driving its own proliferation |
|
|
second way to differentiate into CTL:
|
APC stimulates CD4+ helper, which activates that APC
=> activated APC expresses B7 => signal 2 for T cell prolif/diff |
|
|
third way to differentiate into CTL:
|
APC activates CD4+ helper to make IL-2 and naive T cell to make IL-2 receptors
=> IL-2 secreted by CD4 helper binds to CD8+ T cell => activation |
|
|
how do CTL's kill infected cells?
|
they make granzymes that enter the cell through a pore
=> caspase cascade => apoptosis |
|
|
**activated helpers and CTL's migrate to:**
|
the site of inflammation
|
|
|
***unlike effector cells, _________________ is NOT required to activate memory cells***
|
signal 2;
=> *rapid response* to second infection |
|
|
when do CD4+ and CD8+ cells become memory cells?
|
during differentiation
|
