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pathophysiology > lecture 7: B-cells, hypersensitivity/ allergy, and autoimmune diseases > Flashcards

lecture 7: B-cells, hypersensitivity/ allergy, and autoimmune diseases Flashcards

1
Q

the body’s defense mechanisms: 2 branches od adaptive immunity

A

HUMORAL IMMUNITY (B cells)
- produce Ab
- main defense against EXTRACELLULAR bacteria and bacterial toxins

CELL MEDIATED IMMUNITY (T cells - CD8 and CD4)
- form pop’n of lymphocytes that attack and destroy infected cells (CD8)
- main defense against viruses, INTRACELLULAR bacteria
- eliminating abnormal cells that arise in cell division (cancer)

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2
Q

response of lymphocytes to foreign antigens

A

entry of foreign antigen into body triggers chain of events:

  1. recognition of foreign antigen
  2. proliferation of individual lymphocytes that are programmed to respond to antigen from a large group (clone) of cells (and differentiation)
  3. destruction of pathogen/ infected cells by responding lymphocytes (increased humoral and cell-mediated immunity) (eliminate antigens)
  4. contraction (homeostasis) - apoptosis
  5. memory
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3
Q

interaction of humoral and cell-mediated immunity

A

when appropriately stimulated…

  • T lymphocytes proliferate to form a diverse population of cells that regulate the immune response and generate a cell-mediated immune reaction to ELIMINATE ANTIGEN (CD4/CD8)
  • lysis (use APC, MHC, etc…)
  • B lymphocytes proliferate and MATURE into ANTIBODY-FORMING PLASMA CELLS - require CD4 T CELL HELP
  • they don’t need MHC, can work on their own
  • neutralization, lysis (complement), phagocytosis
  • both retain some cells as MEMORY CELLS
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4
Q

B lymphocyte response to antigen

A
  • have immunoglobulin molecules (BCR) on their cell membranes (antigen receptors)
  • they can bind entire antigen molecules to their receptors (do not require MHC presentation!!)
  • move into cell and is process into fragments
  • fragments displayed on cells’ membrane w MHC II !!!
  • presentation and recognition of antigen by CD4 which upregulates and enhances Ab production

*each B cell has 1 unique B cell receptor!
* B cell –> plasma cell (Ab) or memory B cell

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5
Q

antibodies

A
  • GLOBULINS produced by plasma cells
  • lots in PLAMSA, 10-20% of plasma proteins in circulation
  • can only react with the SPECIFIC ANTIGEN that induced its formation (binding to BCR)

they are everywhere, similar to complement but more powerful

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6
Q

functions of antibodies

A
  • activation of complement (MAC complex -> destruction)
  • neutralization (block the sites on bacteria or viruses they use to enter)
  • agglutination (binding/ clustering of pathogens)
  • opsonization (enhance phagocytosis via tagging)
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7
Q

antibody structure

A

4 protein chains
- 2 light (small) - top
- 2 heavy (large) - stock

T shaped before binding antigen

Y shaped after binding antigen

antigen binds to arms of molecule (top)

carbs in there too

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8
Q

4 types of antibodies (immunoglobulins)

A

IgG
IgA
IgM
IgE
IgD

(GAMED)

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9
Q

IgG

A
  • small, everywhere in body
  • only Ab crosses PLACENTAL BARRIER
  • principal Ab molecule in response to MAJORITY of infectious agents
  • LATER PRODUCTION (shows up later in blood!!)
  • MONOMER

secreted by plasma cells in blood, able to cross placenta into fetus, shows up later

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10
Q

IgM

A
  • large, macroglobulin
  • EARLY PRODUCTION (before IgG!)
  • amplification of COMPLEMENT response (innate)
  • combines with FUNGI
  • PENTAMER (in blood and lymph)

may be attached to surface of B cell or secreted into blood. Responsible for early stages of immunity

when you get infected with something, IgM goes first (iMmediate), then IgG goes after

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11
Q

IgE

A
  • minute (small) quantities in blood
  • binds MAST CELLS, BASOPHILS/ EOSINOPHILS
  • concentration increased in ALLERGIC individuals
  • important in controlling PARASITIC infections
  • MONOMER

parasite protection (parasitic worms), responsible for allergic reactions

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12
Q

IgA

A
  • produced by antibody-forming cells in respiratory and GI mucosa (GI/ RESPIRATORY AND UROGENITAL TRACT)
  • present in SALIVA, TEARS, BREAST MILK
  • combines with harmful ingested or inhaled antigens, forming ANTIGEN-ANTIBODY COMPLEXES
  • DIMER

mucosal/ bronchial - in saliva, tears, breast milk. Protects against pathogens

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13
Q

IgD

A
  • minute (small) quantities in blood
  • on cell membrane of B LYMPHOCYTES
  • functions as a BCR!
  • MONOMER

component of B-cell receptor, activates basophils and mast cells!

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14
Q

Antibody production - B cells

A

NAIEVE B cells on BCR on cell surface

recognition of ANTIGEN = activation (upregulates molecules similar to dendritic/ macrophage cells (APC)

processed antigen is presented on MHCII - recognition - binding to CD4 (and COSTIMULATORY molecules) for same antigen

then stimulates TRANSITION TO PLASMA CELL (which makes Ab):
- proliferation/ increased Ab production
- class switching - specialized effector functions
- affinity maturation - competition/ mutation (stronger affinity to antigen)
- memory (travel to spleen/ BM)

without T cell help - Ab production is weak and short-lived! (COSTIMULATION makes it more powerful)
- CD4-Bcell (TCR, CD40L, cytokines)
- costim. activates B cell (B cell clonal expansion and differentiation to plasma cell)
- NEED CD4 AND COSTIM FOR THINGS TO HAPPEN

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15
Q

adaptive immunity is an awesome weapon that….

A
  • allows vertebrates to have extended life spans due to INFECTION CONTROL OF VARIOUS PATHOGENS
  • also the tool that modern medicine had taken great advantage of with the emergence of vaccination
    (vaccines don’t give you anything, they just wake up the immune system)
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16
Q

methods of control of the immune system

A

activating and preventing overactivation

  1. CYTOKINES (direct/ control immune response)
  2. TOLERANCE (central/ peripheral, don’t react to yourself)
  3. REGULATORY CELLS (specific T cells regulate)
  4. ACTIVATION VS ANERGY/ APOPTOSIS (cell death)
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17
Q

loss of control/ chronic activation leads to…

A

risk of HYPERSENSITIVITY OR AUTOIMMUNITY

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18
Q

immune control: cell anergy

A
  • once infection has been effectively controlled, it is vital to SHUT OFF immune responses
  • any immune activation = risk of loss of control
  • develop hypersensitivity or autoimmunity
  • lack of response from lymphocytes… when T/B cell encounters antigen without costimulation
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19
Q

indirect cell anergy

A
  • due to less antigen present to stimulate immune response
  • DCs die after a few days
  • without support from macrophages/ DCs, activated cells will die off

(chat - indirect cell anergy is a protective mechanism that occurs when there is insufficient antigen and support from other immune cells, leading to the functional inactivation of previously activated lymphocytes)

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20
Q

direct cell anergy

A
  • apoptosis and molecular inhibition of immune functions (activated T cells are inherently pro-apoptotic)
  • TIM-3, PD1/PD1L, CTLA-4
  • chronic activation of T cells results in up-regulation of THESE MOLECULES that produce intracellular signals that deactivate immune cells
    (T cells are active which increases levels of TIM-3 and others, which stimulates them to die and DECREASE IMMUNE SYSTEM)

chat:
(functional inactivation of T cells through two primary mechanisms: apoptosis (programmed cell death) and molecular inhibition of immune functions)
(chat - apoptosis: Activated T cells can become inherently pro-apoptotic, meaning they are predisposed to undergo programmed cell death. This is a crucial regulatory mechanism to prevent excessive immune responses that could lead to tissue damage or autoimmunity)

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21
Q

IL-2

A
  • produced by T cells
  • major growth factor for T cells
  • promotes growth of B cells
  • acts on T cells in paracrine/ autocrine fashion
  • activation of T cells results in expression of IL-2R and production of IL-2
  • promotes cell division
  • proliferating cytokines for T-cells
  • proinflammatory (Th1)
  • upregulates immune system
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22
Q

IL-4

A
  • produced by macrophages and Th2 cells
  • stimulates development of Th2 cells from naive Th cells and promotes the growth of differentiated Th2 cells –> antibody response
  • antiinflammatory (Th2) (Ab producing - same with IL-5)
  • upregulates (suppress) the immune system
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23
Q

IL-5

A
  • produced by Th2 cells
  • promotes growth and differentiation of B cells and eosinophils
  • activates mature eosinophils
  • antiinflammatory (Th2)
  • upregulates (suppress) immune system
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24
Q

TGF-B

A
  • transforming growth factor beta
  • produced by T cells and many other cells
  • INHIBITORY CYTOKINE
  • inhibits proliferation of T cells and activation of macrophages
  • BLOCKS effects of pro-inflammatory cytokines!
  • antiinflammatory (Th2) - shut down immune response
  • DOWNREGULATES IMMUNE RESPONSE
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25
Q

IFN-Y

A
  • important cytokine produced by Th1 cells
  • also produced by Tc and NK cells (less)
  • functions in innate and adaptive
  • proinflammatory (Th1)
  • upregulates immune system
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26
Q

Th1 vs Th2

A

cytokines polarize the immune system response to deal with encountered pathogens

  • polarize through Th1 and Th2
  • immune system tips more towards cellular or humoral immunity based on what cytokines are produced
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27
Q

Th1

A

CELL BASED
- VIRAL/ BACTERIAL attacks in BLOOD and TISSUES
- polarize cells of adaptive and innate to promote cellular immunity
- most effective against these invaders
- PROINFLAMMATORY

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28
Q

Th2

A

HUMORAL-ANTIBODY
- PARASITIC/ MUCOSAL infections
- Ab based
- basis of hygiene hypothesis, allergy IgE
- ANTIINFLAMMATORY

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29
Q

positive and negative feedback for Th1 and Th2

A

cytokine effects are local and travel to sites of infection

positive feedback: Th1/2 cytokines enhance and encourage Th1/2 functions and uncommitted cells (IL-2, IL-4)

negative feedback: Th1 inhibits Th2 function and vice versa (IFN-y, IL-10)

30
Q

development of T and B lymphocytes

A

1.stem cells –> bone marrow
2.hematopoietic stem cells mature in bone marrow
3.
- some stem cells become MYELOID progenitors (into RBC and most WBC)
- other stem cells become LYMPHOID progenitors (into B, T, NK cells)

  1. (“other”)
    B-cell differentiation (bone marrow) –> mature naive B-cells go to OUTER cortex of LN

T-cell differentiation (thymus) –> mature naive T-cells go to PARACORTEX of LN

31
Q

central tolerance

A

B and T cells must:
- NOT react to self antigens
- be restricted to self MHC molecules (T cells), so they will only react to presented antigens (not attack self)

*they must learn not to attack itself, but tolerate itself (central = bone marrow/ thymus)

immature lymphoid progenitor (T cell) from bone marrow enter the thymus from the blood
- B-cells remain in bone marrow as they develop/ mature
- begin to proliferate and rearrange gene segments of the TCR gene to generate a TCR repertoire - incredible diversity (get their own receptors to things)

pos selection: select for recognized MHC
neg selection: select against self-antigens

32
Q

positive selection- MHC RESTRICTION

A
  • selection by epithelial cells in cortex that express MHC molecules with peptides
  • cells that recognize MHC peptide complexes receive RESCUE SIGNALS that PREVENT APOPTOSIS (POSITIVE SELECTION - CD4 AND CD8 RECEPTORS)

T-cells that recognize MHC (II and I respectively) restriction migrate to medulla of THYMUS (for neg selection)

*select for recognized MHC
*T cells start as double negatives (no receptors)
*T-cells are double positive (receptors for CD4 and CD8)
*try to recognize MHC 1/2 and differentiates into CD4 or CD8 (single positive - 1 receptor)
*if it doesn’t recognize either, it dies

33
Q

negative selection-SELF

A
  • THYMIC DCs (APCs) present SELF peptides acquired throughout body
    (gene presents self-proteins on the surface - T cells (other than Treg) that react to it die)
  • AIRE (autoimmune regulator) gene causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues
  • antigens presented by thymic dendritic cells are a SNAPSHOT of current self antigens in the body
  • T cells that bind to these MHC/ self-peptide complexes are DELETED

*select against self-antigens (if it recognizes self, it is killed)
*any cell (other than Treg) that recognizes self, dies
*getting rid of the cells that react to your own body cells

34
Q

Regulatory T cell generation (Treg)

A
  • in thymus
  • subset of CD4 cells with a SLIGHTLY HIGHER AFFINITY FOR SELF ANTIGENS (during neg selection) BECOME nTreg cells!!
  • 5% of CD4 cells in circulation are naturalTreg
  • nTreg cells stop CD4 and CD8 cells from attacking self antigens
  • inducible or adaptive Treg cells can be generated to SELF and FOREIGN antigens after an inflammatory immune response (helping with inflammatory immune response)
  • recognizing self is good for nTregs!

*effector cells turn into Tregs to shut down immune response
*recognition in thymus (central) or peripheral can turn into Tregs –> inhibition of T cell activation or T cell effector functions

35
Q

peripheral tolerance - regulatory T cells

A

Treg cells
- regulate activation of other T cells
- necessary to maintain peripheral tolerance to self-antigens
- CD4+CD25+ FoxP3+
- produces cytokines that shut down the immune system (IL-10, TGFB)
- both of these cytokines bind surface receptors on activated T cells initiating a signalling cascade that deactivates the cell

inhibitory cytokines
cytolysis
metabolic distruption
targeting DCs

36
Q

T cell maturation

A

you have a lot of T cells, only some of them mature!! 2-3%

  • out of 60 million T cells produced per day, 2 million survive to exit the thymus as MATURE T cells (2-3%)
  • the rest are deleted by apoptosis and consumed by macrophages
  • fetal development - full complement when born, activity of thymus decreases over time with large drop in thymic function after puberty
37
Q

B cell central tolerance

A

B cells undergo similar developmental selection in BONE MARROW!!!
- less strict central tolerance than T cells (30-40% survive) - continued development throughout life

positive (proper function signalling of BCR)
- will activate B cell maturation
negative (reaction to self) recognition of self
- results in receptor editing -SECOND CHANCE FOR BCR REARRANGEMENT

B-cell development is not MHC restricted but they are indirectly MHC restricted
(FOR B-CELLS TO BE ACTIVATED, THEY NEED ACTIVATION FROM CD4 - licensing)

since B cells present antigens with MHCII to CD4 T cells, additional selection against self is gained from T cell recognition
(B cells are dependent on T cells to be activated - dependent relationship)

38
Q

tolerance - B lymphocytes

A

central tolerance (bone marrow) 50-70% autoreactive
- most tolerance happen here
- you have self-reactive B cells –> some die (apoptosis), some do receptor editing (one more chance to make good receptor), some escape to peripheral

peripheral tolerance (lymphoid organ: spleen, LN) 20-30% autoreactive
- hopefully they get shut down here
- energy, follicular exclusion, apoptosis

39
Q

B cell tolerance - peripheral

A

B cells can present antigens through MHC II to CD4 helper T cells

  • recognition by T cell results in CO-SIGNALLING (CD40L) and release of cytokines that will activate the B-cell (costimulation with B cell)
  • co-receptor signals can also be received from the presence of microbial components/ complement
  • lack of co-receptor signals = ANERGY/ DEATH/ COMPARTMENTALIZATION

when costimulation between B and T cells doesn’t happen in B cell tolerance, the B cell dies and can’t be activated

40
Q

peripheral tolerance - T cells

A

not much in blood, most in LN
- naive T cells stay in CIRCULATION, don’t stay in LN or tissues so they only encounter a portion of antigens in our body (compartmentalization)

  • all antigens aren’t recognized in thymus

REPEATED STIMULATION AND NO COSTIMULATION (from innate immune cells) = DEATH (anergy/ apoptosis)

  • no single method is perfect, but combined they have great effectiveness so autoimmune disorders are relatively rare

*you need a mechanism in the periphery to inactivate T and B cells because some antigens aren’t central (Bone marrow/ thymus)

41
Q

self-regulation - competition receptors for activation of T cells

A

T cells are activated by high affinity TCR engagement with MHC peptide complexes!!!

  • THEY ALSO REQUIRE CO-STIMULATION TO BE ACTIVATED
  • T cells express high amounts of CD28 on surface and CTLA4 is stored intracellularly
  • as T cells are stimulated they UPREGULATE CTLA4 molecules on the cell surface which out compete CD28 for B7 molecules (CD80/86)
  • CTLA4 is STRONGER THAN CD28 (1000x affinity)
  • CTLA4-B7 binding makes less B7 molecules available for interaction with CD28 and binding represses activation and blocks CD28 signalling
  • PD1 and various pro-apoptotic molecules are also upregulated
  1. costimulation needs to happen when T cell is activated to stop T cell repsonse that is reacting with self antigen
  2. more likely to have CTLA4-B7 than CD28-B7 which stops immune response
  3. competition of coreceptors makes sure T cells don’t upregulate (turn down immune response from CTLA4-B7 outcompeting CD28, which’s costimulation initially activated T cell)

*receptors may compete for coreceptors when T-cell is activated - makes sure T cells don’t upregulate… the longer a T cell is activated, the more apoptotic things are

42
Q

hypersensitivity reactions

A

failure in tolerance or immune control mechanisms can lead to development of hypersensitivity reactions

environment - allergy
self - autoimmunity

43
Q

failures of adaptive immunity

A

type I: allergy (immediate)
type II: cytotoxic
type III: immune complex
type IV: delayed hypersensitivity or cell-mediated hypersensitivity

44
Q

hypersensitivity reactions: type I

A

ALLERGY AND ANAPHYLAXIS (immediate) IgE
- allergy FIRST develops through sensitization
- IgE loading on mast cells, basophils, eosinophils (preloading)!!!
- LATER contact with same antigen triggers release of mediators (HISTAMINE) and related clinical manifestations (sensitization)
(localized response like hay fever, food allergy (peanuts), pets, mold)

45
Q

hypersensitivity type 1 continued. (rxn type, treatment, and antihistamines)

A

mild reaction: uticaria (rash), itching, swelling (edema)

treatment: environmental control, antihistamines, steroids, leukotriene inhibitors (stops cytokine action), allergen immunotherapy (immune tx - allergy shots)

antihistamine: drugs often relieve allergic symptoms, histamine is one of the mediators released from IgE-coated cells
(allergy shot –> peripheral tolerance –> present body with higher and higher doses of antigen)

46
Q

hypersensitivity: type 1 - anaphylaxis

A

hypersensitivity reaction that may be life-threatening (too much histamine release)

systemic response: seafood/ peanuts, bee sting, penicillin

sensitizing agent (ex. cashews) circulates body, triggers widespread mediator release from Ig-coated mast cells and basophils
- may lead to anaphylaxis: SEVERE GENERALIZED IGE-MEDIATED REACTION (FALL IN BLOOD PRESSURE, SEVERE RESPIRATORY DISTRESS)
- unpredictable can be BI-PHASIC (sometimes later in time there can be another phase - another anaphylactic reaction after the first one when you think it’s over)
- PROMPT treatment required with EPINEPHRINE for anaphylaxis

47
Q

hypersensitivity: type 1 susceptibility

A

GENETIC
- multifactoral (environment, genetics, bad luck)
- can be passed on from parents

ATOPIC PERSON
- allergy-prone individual (atopic march)
- if you have eczema, rhinitis, asthma, or food allergy you are more likely to have more than one of them
(when you get older, some go away, same genetic profile, can be passed down)

ENVIRONMENTAL
- hygiene hypothesis
- hypersensitivity, asthma and autoimmune diseases are much LESS common in the DEVELOPING world compared to the industrialized world
- more modern clean sterilized cultures have more allergies where there is no sterilization (since our immune system isn’t constantly working) - exposure to pathogens/ dirt is good

Th2 MEDIATED, B-CELLS, IGE (IL-4/ IL-5, TGF-B)

48
Q

hypersensitivity: type II

A

CYTOTOXIC - ANTIBODY DEPENDENT (IgM, IgG)

  • antibody COMBINES with cell or tissue antigen, resulting in COMPLEMENT-MEDIATED LYSIS of cells or other membrane damage from activated CTL
  • ex. autoimmune hemolytic anemia, blood transfusion reactions, Rh hemolytic disease, autoimmune glomerulonephritis

*neutrophils and other things attack and destroy cells
*CAN BE AUTOIMMUNE

49
Q

hypersensitivity: type III

A

IMMUNE COMPLEX - IgM/ IgG
- IgM/IgG Ab-Ab immune complexes DEPOSITED in tissues activates COMPLEMENT PATHWAY
- neutrophils attracted to site causing TISSUE DAMAGE
- ex. rhematoid arthritis, systemic lupus erythematosus (SLE), some types of glomerulonephritis

*immune complex is formed by Ab/ antigens –> tag for destruction –> cause inflammation and damage

50
Q

hypersensitivity: type IV

A

cell mediated (T cells), DELAYED hypersensitivity (24-72h)

  • T-cells are SENSITIZED and activated on second contact with same antigen
  • Th1 lymphokines induce inflammation and activate MACROPHAGES AND CTLS (CD8)
  • ex. contact dermatitis, diabetes mellitus (T1), rheumatoid arthritis

*takes days to develop, not quick to react
*T-cells recognize antigens and destroy
*NOT IgE (that’s only for immediate)
*sensitize (cause something to respond to certain stimuli; make sensitive)

51
Q

autoimmunity

A
  • not enough tolerance to self antigens (defect in mechanisms meant to preserve tolerance to self antigens)
  • 2-5% of people develop

CAN OCCUR WHEN:
- express MHC with self-peptides
(2 types of MHCII increase chance of T1D by 20 fold)

  • produce T or B cells that have receptors that recognize self
    (random mix match, even identical twins will not share TCR repertoires - chance)
  • breakdown of tolerance mechanisms that should eliminate self

GENETIC DEFECTS
- can lead to failures of immune control/ balance between activation and control
- most due to failure of self-tolerance mechanisms which lead to production/ survival of self reactive cells
- could be due to a constellation of genetic effects
- 20-50% in identical twins, 2-5% in nonidentical twins or siblings) - genetics don’t play a huge role

52
Q

autoimmunity continued

A

breakdown in immune function/ tolerance
- defects in central tolerance deletion/ survival
- defects in Treg functions/ numbers
- defective apoptosis mechanisms (+/-‘ve)
- not enough inhibitory receptor functions (CTLA/ Fas)
- chronic activation of APC’s, excessive T cell activation

tend to be CHRONIC, PROGRESSIVE, and SELF-PERPETUATING!! (if adaptive… also gets worse as you age)

53
Q

autoimmunity: complex polygenic traits

A

GENES, ENVIRONMENT, IMMUNE REGULATION
- if any of these goes wrong –> AUTOIMMUNITY

complex polygenic traits contribute to development of autoimmunity (characteristic influenced by more than 1 gene)

  • constellation a genetic polymorphism contribute to disease susceptibility combined with environmental factors lead to disease development
54
Q

molecular mimicry - moms definition

A

when a T cell/ B cell receptor recognizes a virus or bacteria…

and when an outside antigen (virus/ bacteria) and self antigen look similar…

T cell might react against self from the trigger of a virus/ bacteria because self looks similar (it wanted to react against a virus or bacteria but it was actually a self-antigen that looked like it was foreign)

“cross-react” - self and antigen

ex. when you get strep (bacteria), your body makes Ab against strep which looks similar to self heart antigens. Abs attack self heart tissue creating an immune response (it wanted to attack the strep, but they looked too similar)

55
Q

molecular mimicry - faller definition

A
  • any TCR or BCR is generated randomly and can recognize different antigens with varying efficiencies with potential to CROSS REACT (self and antigen)
  • potential for certain self antigens to also be recognized by cells that recognize pathogens (virus/ bacteria)
  • infection awakens these self reactive cells and provides necessary inflammatory environment (INHIBITS PERIPHERAL TOLERANCE)
  • autoimmune diseases frequently FOLLOW bacterial or viral infections probably due to predisposing conditions (genetic/ environment) combined with immune activation (provides COSTIMULATION that would otherwise be absent)
    *bacteria stimulates Ab which cross-react with heart tissue (infection created an immune response which attacks self)

rheumatic heart disease: T cells that recognize streptococcal antigens cross-react with tissues of the mitral valve of the heart (a T cell can recognize viruses and self-antigens)

56
Q

model of autoimmunity development

A
  1. genetic susceptibility (create T or B cell but sitting in LN)
  2. failure of self tolerance/ immune control
  3. infection/ injury
  4. activation of APCs (viral and bacterial stuff is presented)
  5. recruitment of auto-reactive lymphocytes
  6. activation of auto-reactive lymphocytes
  7. tissue injury from autoimmune attacks
  8. autoimmune disease

*The whole immune system reacts to self-antigens in a susceptible person
*T cells go around and cause problems

57
Q

autoimmune diseases: organ specific - INSULIN DEPENDENT DIABETES MELLITUS

(KNOW ALL THESE DISEASES!!)

A
  • immune system targets insulin producing beta cells in pancreas (Islets of Langerhans)
  • mediated predominantly by CTL (CD8) activity, B cells also play a role
  • CTLA-4 genetic defects have shown to increase susceptibility
  • dysfunctional nTreg
58
Q

autoimmune diseases: organ specific - MYASTHENIA GRAVIS

A
  • self-reactive antibodies bind to acetylcholine receptors (acetylcholine then can’t transmit things to another cell)
  • results in muscle weakness and paralysis
  • polio proteins could be molecular mimics for acetylcholine receptors
    (get into brain)
59
Q

autoimmune diseases: organ specific - MULTIPLE SCLEROSIS

A
  • CNS inflammatory disease
  • initiated by reactive T cells/ macrophages
  • chronic inflammation destroys myelin sheath protein, causing defect in sensory inputs
  • cells that react to myelin basic protein also react to proteins from EBV and herpes simplex virus (molecular mimicry?)
  • particular MHC II allele associated with increased risk (HLAD1 1501)
    (can’t propagate signal, T-cell destroys sheaths)
60
Q

autoimmune diseases: systemic - RHEUMATOID ARTHRITIS

A
  • systemic autoimmune disease
  • cartilage protein targeted causing chronic joint inflammation
  • reactive T cells form patients also recognize mycobacterium TB protein (cross reactive?)
  • IgM, IgG antibody complexes form in joints and activate macrophages –> complex stimulates immune response against self-antigens)

*all over body, molecular mimicry with tuberculosis

61
Q

autoimmune diseases: systemic - LUPUS ERYTHEMATOSUS

A
  • systemic rash (forehead/ cheeks), inflammation of lungs, kidneys, joints, paralysis, convulsions
  • breakdown in both T and B cell TOLERANCE
  • production of diverse IgG antibodies against a range of DNA, DNA protein complexes, RNA-protein complexes that clog organs and cause chronic inflammation
  • more than a dozen MHC alleles have been identified that contribute to development (lack of activation-induced cell death may play a role)
62
Q

development of autoimmune disorders is…

A

POLYGENIC AND MULTIFACTORIAL

  • genetic mutations associated with autoimmune disorders:
    Treg(FoxP3)
    Cell activation (IL-2, IL-12, CD2/58, Blk)
    Activation inhibitors (IL-10, CTLA4)
    Apoptosis (Bim, Fas) - cells not dying
    HLA alleles (MHC) - different MHC receptors

*there is no one receptor for a gene/ disease

63
Q

latitude and autoimmunity

A

MS, T1D, RA, Chron’s, SLE, Autoimmune Hep, etc…

  • latitide? UV radiation? skin tone? obesity? temperature? genetics? VITAMIN D?

VITAMIN D HAS THE MOST EVIDENCE!! (significant correlation)
- vitamin D = immune MODUATING hormone, and has been shown to influence autoimmune diseases
- intake of vitamin D has shown a degree of PROTECTION/ REDUCED SYMPTOMS
-deficiency has been associated with increased autoimmune disease frequency

64
Q

TH1 vs TH2 imbalance: hygiene hypothesis

A

reduced exposure to parasites because of improved hygiene, which in turn increases the RISK OF ALLERGY AND AUTOIMMUNITY

65
Q

TH1 vs TH2 imbalance: helminths

A

parasitic worms, PROMOTE TREG FUNCTION and produce a number of immune modulating factors to defend itself (co-evolved)
- roundworms, tapeworms, flukes, whipworm, hookworm

autoimmunity (Th1) arises due to decreased infection encounters with worms/ parasites polarize the immune system to Th2 profile
- if you have more parasitic infections, you are more likely to have a Th2 reaction!!!

clinical trials have shown that HELMINTH THERAPY (giving helminths) can improve symptoms in autoimmune and inflammatory diseases , by SUPPRESSING immune responses
(infect people with worms to suppress immune response)

66
Q

autoimmunity in women disproportionately affecting WOMEN

A

women are MORE SUSCEPTIBLE TO AUTOIMMUNE DISEASES
- probably related to X-linked gene

SEE REST OF SLIDE FOR MORE INFO

67
Q

role of XX chromosomes in autoimmunity

A
  • dosage of X chromosome appears to be a major driver of autoimmune risk irrespective of sex or hormonal status
  • patients with Kleinfelter (XXY) are phenotypically males, have male hormonal pattern, but have elevated risk of autoimmune disease equivalent to females

X SILENCING by Xist - transcribed from inactivated X chromosome play a key role
- Xist Ribonuclear protein complexes function as antigenic triggers causing greater prevalence of autoimmune diseases in females
- expression of Xist RNPs in male mice is sufficient to increase autoimmune disease severity
- silenced X also has some limited gene expression - specific X-linked genes, such as TLR7, can escape X inactivation and may contribute to development of…
*cell death –> Xist RNP

*silenced X chromosome may be responsible for things expressed?
*people who have XXY have an elevated risk of autoimmune disease - maybe this is why women are more susceptible - BECAUSE THEY HAVE X

68
Q

autoimmune treatments

A

no cure, just things that block immune response

symptomatic

pain control/ physical therapy

immunosuppression therapy
- corticosteroids/ ANTIinflammatory
- chemical T cell/ B cell inhibitors/ cytokine blockers
(Il-2)
- immunotherapy: mAb to block immune receptors on T/B cells or cytokines (TNF-a)
(dampen immune response, makes you susceptible to other things… vaccinations help the side effects of of immunotherapy/ things you may be susceptible to now)
- IVIG (block Fc receptors on cells)

69
Q

autoimmunity conclusion

A

ADAPTIVE immune system
- a powerful weapon we use to defend against lots of foreign pathogens

control of ADAPTIVE IMMUNITY
- cell anergy/ apoptosis (SPECIFICITY)
- tolerance to self antigens (peripheral/ central)
- direction/ control of cytokines
- control/ suppression of immune response (Treg, CTLA4, apoptosis)

failure of ANY of these mechanisms –> potential development of ALLERGY OR AUTOIMMUNITY
- more failures = greater chance

even without genetic predispositions, potential development of autoimmunity still exists (genes, environment, immune regulation)
- autoimmunity can be a failure from ANY of these (any tolerance)

70
Q
A

pathophysiology (10 decks)

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