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New stuff Flashcards

1
Q

Common allergens

A
  • inhaled materials: plant pollen, dust mite feces
  • injected material: insect venom, drugs
  • ingested material: peanuts, shellfish
  • contacted materials: plant oil, metal
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2
Q

Type I hypersensitivity

A
  • Allergen binding to IgE bound to mast cells, basophils and eosinophils.
  • Cells explosively and rapidly degranulate releasing proinflammatory mediators.
  • Pollen allergy, anaphylactic shock
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3
Q

Type II hypersensitivity

A
  • Small molecule binds to and modifies host cell.
  • B cell IgG response to modified component on host cell.
  • Complement activation and phagocytosis causes inflammation and tissue damage. Penicillin
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4
Q

Type III hypersensitivity

A

-Ab response to soluble protein
Immune complexes deposit on walls of small blood vessels and lung tissue.
Inflammation.
-Administration of bovine insulin to diabetics, also administration of therapeutic antibody

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5
Q

Type IV hypersensitivity

A
  • Th1 or CD8 T cell response to modified proteins.
  • Response take a few days to develop.
  • Poison ivy, metal allergies
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6
Q

The physiological basis for Type I hypersensitivity

A
  • IgE-driven degranulation is an important defense against helminths (parasitic worms)
  • Parasitic worms have probably played a major role in human evolution
  • Their large size makes them resistant to direct killing by CTL, macrophages, antibodies
  • The immune system seems to be directed at stimulating physiological and behavioral mechanisms involved in expulsion from the body (diarrhea, sneezing, coughing, vomiting, scratching)
  • Favored by Th2 responses. IL-4 is an important isotype switch factor for IgE. IL-5 is an important factor that increases eosinophil production from bone marrow
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7
Q

Parasitic disease prevalence

A
  • Parasitic infections are endemic in tropical countries
  • 1.5 billion people infected with helminths
  • Incidence greatly reduced in developed countries
  • Inversely correlates with allergic and autoimmune disease
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8
Q

IgE and FceR1 have unique properties that enable arming of mast cells

A
  • IgE is mostly present bound to high affinity FceR1 on mast cells in tissues
  • FceR1 is a tetramer of one binding molecule and 3 signaling molecules
  • IgE is held in a rigid “shrimp” like structure through the Ce2 domains which are unique to IgE (no hinge regions, so no flexible Y shape)
  • Extremely high affinity interaction that arms mast cells for binding to antigen
  • During an antibody response involving IgE, mast cells soak up IgE and maintain a depot of cell-bound antigen-free IgE.
  • In this way, mast cells express a variety of antigen-specific receptors of different specificities (co-evolution of innate and adaptive immunity!)
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9
Q

IgG and its isotypes

A
  • IgG overall very flexible molecules: Easier access to antigenic determinants
  • Amino acid differences between IgG isotypes tend to be concentrated in Ab hinge regions
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10
Q

Mast cells versus B cells

A
  • B cells have once specificity and there are 50,000-100,000 per cell
  • Mast cells have many passively acquired specificities and there are 0.5 million per cell
  • helminth endemic areas have receptors for worms, developed areas have receptors for pollen
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11
Q

Cross linking mediated by IgE and antigen stimulates degranulation

A
  • Mast cells contain preformed granules packed with inflammatory substances
  • They are rapidly released upon FceR1 cross-linking
  • Also in response to cross-linking, mast cells initiate synthesis and release of proinflammatory mediators. A slower process
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12
Q

Therapeutic anti-IgE as a way to treat IgE mediated allergy

A
  • anti IgE prevents mast cell from acquiring cell-surface IgE. Mast cell cannot be activated through FCERI and downregulates its cell surface expression
  • anti IgE cross links IgE bound to FCERI and activates mast cell degranulation. Inflammatory response
  • Omalizumab (anti-human IgE) prevents binding to high affinity FceRI. At the same time does not bind (or cross-link) surface-bound IgE because it recognizes the region of IgE that binds FcR.
  • Experimental anti-IgE binds to regions of IgE not involved in Fc binding, and induces degranulation
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13
Q

Immunoglobulins as tools: Monoclonal antibodies

A

*** look at slide

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14
Q

mast cells

A
  • FceRI, TLR’s, also Fc receptors for IgG and IgA
  • Only FceRI directs degranulation
  • Other receptors induce expression of specific genes
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15
Q

Mast cell function

A
  • immediate histamine release: increase vascular permeability, smooth muscle contraction and increased mucus secretion
  • synthesis of eicosanoids from lipid precursors: similar function as histamine, delayed but more potent
  • TNFa- preformed and newly synthesized, increased endothelial adhesion molecules= increased inflamation
  • -All lead to inflammation, explosive physiological reactions
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16
Q

Eosinophil responses

A
  • Express FceRI only after inflammatory response has been initiated
  • IL-5 (Th2 product) released by mast cells stimulates increased eosinophil production from bone marrow
  • Recruited to site of inflammation by CCL11 (eotaxin)
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17
Q

Basophils: Rare and mysterious cells

A
  • Only 1% of leukocytes. Circulate in blood (unlike mast cells which are found in tissues)
  • Produce mediators similar to mast cells
  • Developmentally seem more closely related to eosinophils (shared growth factors, common stem cell precursor)
  • There is evidence that they initiate Th2 responses through IL-4 production, although this is controversial
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18
Q

Mast cells, eosinophils and basophils work together to enhance inflammatory response

A
  • trigger
  • tissue mast cell
  • degranualation inflammation, recruitment of eosinophils, basophil
  • eosinophil degranulation, release of major basic protein (MBP)
  • MBP stimulates basophil and mast cell degranulation
  • MBP stimulates basophil and mast cell degranulation
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19
Q

Nature of allergens

A
  • unclear what makes an allergen

- all allergens triggering type I hypersensitivity are proteins

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20
Q

The process of allergic sensitization

A
  • first exposure to pollen
  • extraction of antigen
  • activation of antigen-specific T cells
  • production of IgE and its binding to mast cells
  • IL 4 stimulates class switching to IgE
  • FC receptor: mast cell are now sensitized for rapid degranulation upon allergen re encounter
  • IL-4 promotes isotype switching to IgE
  • Allergic responses often become more intense with each subsequent re exposure
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21
Q

Anisakis simplex (Herring worm)

A
  • parasitizes ocean fish
  • infects humans, boring through intestinal epithelium and lodging in muscle tissue
  • Muscle cramps
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22
Q

Genetic determinants of allergy

A

-MHC class II genes
-IL4
IL4R
-High affinity IgE receptor B chain

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23
Q

Mothers can transmit IgE responses to unborn child

A
  • Maternal IgE/allergen present in amniotic fluid which the fetus ingests
  • Crosses the fetal gut because epithelium is leaky at this stage
  • By binding to FceR on fetal APC a Th2 response to allergen is potently triggered
  • Through cognate interaction and IL-4 secretion, IgE-secreting B cells induced

-This is a way allergy can be passed to child, but IT IS ALSO A WAY THE CHILD COULD BE PREINSTRUCTED FOR RESISTANCE TO HELMINTH INFECTION

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24
Q

Systemic anaphylaxis

A
  • antigen in bloodstream enters tissues and activates connective tissue mast cells throughout the body
  • Direct injection of allergens into blood (drugs, insect stings) causes widespread and rapid degranulation of mast cells
  • Causes increased vascular permeability (lose of blood pressure = anaphylactic shock) and smooth muscle constriction (in lungs causes asphyxiation). Histamine is the major mediator
  • Some food allergens can rapidly cross gut epithelium and cause anaphylaxis (peanut allergen)
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25
Q

Injection of epinephrine rapidly reverses anaphylactic shock

A

Epinephrine (adrenalin) relaxes smooth muscle contraction, stimulates heart and restores tight junctions between epithelial cells

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26
Q

Systemic anaphylaxis can also be triggered by allergy to penicillin

A
  • penicillin binds to bacterial transpeptidase and inactivates it
  • penicillin modifies proteins on human erythrocytes to create foreign epitopes
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27
Q

Mechanism of penicillin allergy

A
  • complement coated penicillin modified erythrocytes are phagocytosed by macrophages
  • macrophages present peptides from the penicillin protein conjugate and activates specific CD4 T cells to become TH2 cells
  • B cells are activated by antigen and by help from activated TH2 cells
  • Plasma cells secrete penicillin specific IgE which arms mast cell
  • penicillin modified erythrocytes activate armed mast cells causing anaphylaxis
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28
Q

Asthma

A
  • Acute response
  • -mucosal mast cell captures antigen
  • -inflammatory mediators contract smooth muscle, increase mucous secretion by ariway epithelium, and increase blood vessel permeability
  • Chronic response
  • -chronic response mediated by cytokines and eosinophils products
  • Mast cell response to inhaled allergen
  • Acute response can progress to a chronic self-sustaining response mediated by Th2 cells, periodic re-exposure to allergens (Type IV hypersensitivity at this point)
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29
Q

Food allergies

A
  • Ingested allergens can also leave the intestine and cause more systemic effects (e.g. peanut allergy)
  • ingested antigen activate mucousal mast cells
  • activated mast cells release histamine which acts on epithelium, blood vessels, and smooth muscle
  • antigen diffuse into blood vessels and in widely disseminated, causing urticaria. Smooth muscle contration induces vomiting and diarrhea. fluid outflow inot the gut lumen
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30
Q

Three-pronged approach to treating allergy

A
  • Behavior mod: avoid allergen
  • Pharma: anti histamines, steroids, epi
  • Immuno manipulation: Densensitization allergen deviate immunity away from IgE response, anti IgE mAb
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31
Q

Allergy, autoimmunity and the hygiene hypothesis

A
  • Allergy, autoimmunity are rare in non industrialized nations
  • These diseases are common and are becoming more common in the West
  • The original hygiene hypothesis based on the idea that we and our normal microbiota have adapted together through evolutionary history
  • The hypothesis: Early childhood exposure to worms trained the immune system to respond appropriately. Role in induction of regulatory immunological circuits
  • Since been expanded to include a role for microorganisms (e.g., the gut microbiota)
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32
Q

Evidence in support of the hygiene hypothesis

A
  • Mice raised in absence of gut flora are more susceptible to inflammatory gut diseases
  • Mice infected with Th2-inducing helminths are increased in resistance to experimentally induced gut inflammation
  • In northern European countries, people raised in rural farm environment have lowered incidence of allergy compared to urban populations in the same countries
  • Intentional administration of helminth parasites (Trichuris suis; pig wipworms) to patients with inflammatory bowel disease alleviates inflammation – although this is still considered preliminary!
  • Fecal transplants from healthy “donors” to treat inflammatory colitis in humans is beginning to be used in the clinic
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33
Q

The ABO antigens

A

Blood transfusion is the most common type of tissue transplantation (1/4 people)

Donor and recipient must be compatible for the ABO system

Based on glycolipid antigens on the surface of red blood cells AND the fact the commensal bacteria express same carbohydrate antigens

People who are A antigen positive have a response to commensal derived B antigens (and not A because of immunological tolerance). Vice versa for B-positive people

Transfusion with wrong blood type results in destruction of transfused RBC by massive complement lysis and phagocytosis

The immune response triggered in blood type incompatibility is a Type II hypersensitivity reaction

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34
Q

Type I hypersensitivity

A
  • Allergen binding to IgE bound to mast cells, basophils and eosinophils.
  • Cells explosively and rapidly degranulate releasing proinflammatory mediators.
  • Pollen allergy, anaphylactic shock
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35
Q

Type II hypersensitivity

A
  • Small molecule binds to and modifies host cell.
  • B cell IgG response to modified component on host cell.
  • Complement activation and phagocytosis causes inflammation and tissue damage. Penicillin
  • Creates a new epitope and induces mac
36
Q

Type III hypersensitivity

A

-Ab response to soluble protein
Immune complexes deposit on walls of small blood vessels and lung tissue.
-Inflammation.
-Administration of bovine insulin to diabetics, also administration of therapeutic antibody
-infused Ab, induces neutrophil response

37
Q

Type IV hypersensitivity

A
  • Th1 or CD8 T cell response to modified proteins.
  • Response take a few days to develop.
  • Poison ivy, metal allergies
  • Proliferating T cells build up under skin
38
Q

Ig gene rearrangement generates random specificities

A
  • many will be directed against self Ag
  • no reaction with self: immature B cells move to blood and express IgD and IgM
  • Reaction with self: immature B cell is retained in bone marrow
  • negative signal delivered to immature b cell by multivalent ag
  • further development stopped
39
Q

RhD antigens must also be considered in blood transfusion

A

RhD-positive into RhD-negative will induce and anti-RhD response making future transfusions with RhD-positive blood dangerous

Notice that for RhD, the antibody response occurs after transfusion (unlike in the ABO system)

40
Q

Hyperacute rejection of organs can occur due to ABO incompatibility

A

ABO antigens expressed on blood vessel endothelial cells as well as red blood cells

Rapid (within hours) rejection of organ can occur as a result of an extreme class II hypersensitivity reaction

This can also occur when allotype-specific anti-HLA Ab are present in recipient

Allotype-specific anti-HLA Ab can be stimulated in recipient during childbirth (in mother), blood transfusion and organ transplant

Cross-match testing before transplant measures patient serum reactivity to B (to detect MHC class I and II reactivity) and T (to detect MHC class I reactivity) cells from donor

41
Q

Transplant rejection and graft-versus-host disease (GVHD)

A
  • Transplant rejection: recipients t cell attack the transplant
  • GVHD: hematopoietic cells transplanted and t cell in the transplant attack the recipients tissues
  • Both of the above involve T cells and are type IV hypersensitivity reactions
  • Consist of responses to mismatched MHC molecules
  • Polymorphic self antigens (like MHC) are called alloantigens. Transplant between two genetically distinct individuals is an allogeneic transplant. Between two identical individuals (as in identical twins) a transplant is called syngeneic.
42
Q

Organ transplantation is an inherently stressful and proinflammatory procedure

A

Organ from a donor who has died traumatically

Organ is deprived of blood and oxygen during transfer (ischemia), which can trigger inflammation

Recipient undergoes surgical removal of diseased organ. Risk of inflammatory response.

Diseased organ itself likely to have an associated inflammatory response

43
Q

Acute rejection when recipients T cells respond to HLA differences between donor and recipient

A

Type IV hypersensitivity involving CD4 T cells (reacting to HLA class II differences) and CD8 T cells (reacting to HLA class I differences)

Acute rejection occurs over several days as effector T cells proliferate and migrate to organ

Can be minimized with immunosuppressive drugs

44
Q

Immunological mechanism of acute rejection

A

Donor dendritic cells in organ are in an inflammatory/activated state due to stress of surgical removal

Migrate to draining lymph nodes where they encounter recipient T cells.

Alloreactivity: A high proportion of T cells will recognize and respond to polymorphic HLA determinants.

Activated effector T cells return to organ/site of inflammation and mediate destruction

DC migrate to the spleen and activate effector T cells that migrate to the graft via blood and destroy

45
Q

Immunologic basis of alloreactivity

A

During T cell development, T cells have undergone positive selection (weak recognition of MHC) followed by negative selection to avoid strong reactivity with MHC

During positive selection, weak recognition of self MHC means that many of these T cells will by chance strongly react with non-self MHC allotypes

Negative selection eliminates only those TCR that react strongly with self-MHC; TCR reacting with other MHC allotypes remain and enter periphery

Alloreactive T cells recognize MHC determinants involved in TCR/MHC contact. The peptide being presented by donor DC may or may not play a role. 1-10% T cells are alloreactive

46
Q

Chronic organ rejection is a type III hypersensitivity reaction

A
  • Occurs over months or years
  • 50% (over 10 years) of heart and kidney transplants fail due to chronic rejection
  • Characterized by Ab responses to HLA. Deposition of immune complexes on endothelial blood vessels. Chronic inflammation
  • immune complexes deposited in the blood vessel walls of the transplanted kidney recruit inflammatory cells
  • increasing damage enables immune effectors to enter the tissue of the blood vessel wall and to inflict increasing damage
47
Q

Chronic rejection involves an indirect pathway of allorecognition

A
  • apoptotic cell from donor organ with HLA
  • endocytosed
  • antigenic peptide presented by self (recipient MHC) to CD4
48
Q

Generation of anti-HLA Ab during chronic rejection

A
  • Alloantibodies that cause chronic rejection are the result of an immune response stimulated by the indirect pathway of allorecognition
  • produces anti-HLA Ab
  • Activated endothelium from donor organ expresses HLA class I and II, so alloantibodies to both can generated
  • Interesting phenomenon: Indirect pathway can lead to induction of Treg that suppress alloreactive T cells. Patients that previously received blood transfusions from donor with same allotype as a subsequent organ donor have higher Treg activity. This is called the transfusion effect
49
Q

Generalized immunosuppression of recipient before transplant

A
  • Rabbit anti-thymocyte serum
  • Polyclonal reactivity
  • Binds to lymphocytes, NK cells, DC and endothelial cells
  • Works by complement activation and phagocytosis
50
Q

Anti-CD52 treatment (alemtuzamab)

A
  • Target CD52 is GPI anchored in close juxtaposition to cell membrane and expressed by lymphocytes, macrophages and monocytes
  • Complement fixed very efficiently
  • anti CD52 is efficient at depleting leukocytes before organ transplant
51
Q

anti-CD3 mAb (OKT3) pre transplant treatment

A

First mAb used in clinic (1986). Taken off the market in 2008 because alemtuzamab and anti-thymocyte serum work well and increased risk of serum sickness (Type III hypersensitivity) due to high amounts of mAb required

52
Q

Serum sickness is a Type III hypersensitivity reaction

A
  • Can occur when large amounts of foreign Ab are administered
  • Once it occurs, further Ab treatment not possible because a secondary immune response will be triggered causing intensified response
53
Q

Corticosteriod therapy

A

Steroid are lipid soluble compounds that can cross the plasma membrane

Wide ranging effects on gene expression in many cell types

Of relevance to immunosuppression, corticosteroids increase expression of IkB (the inhibitor of NFkB, a proinflammatory transcription factor) and inhibit egress of lymphocytes from bone marrow

Corticosteroids have many side effects due to their non-specific mechanism of action
(prednisone, hydrocortisone)

54
Q

Cyclosporin and tacrolimus specifically block T cell activation

A
  • signals from TCR activate AP1 and increase cellular Ca2+
  • activates phosphatase that activates NFAT
  • NFAT migrates to nucleus bind to AP1 to form an active transcription factor
  • activation of IL2 gene: clonal expansion of T cell
  • drugs act in cytosol, CyP and Tac bind to FKBP
  • FKBP bind phosphotase and prevent activation by Ca+ and blocking NFAT activation: no txn
55
Q

Exploiting CTLA4 to block T cell activation

A
  • Belatacept is an engineered soluble form of CTLA4 used to prevent alloreactive T cell activation (introduced in 2011)
  • alloreactive t cell receptor binds foreign MHC and generates signal 1
  • belatacept binds B7 and prevents engagement of CD28 and generation of signal 2
56
Q

Anti-CD25 therapy works by blocking IL-2 signaling in activated T cells

A

Basiliximab and daclizumab are both anti-CD25 mAb

The benefit of these therapies is that they only target activated T cells so generalized immunosuppression is minimized

Anti CD25 does not bind to low affinity IL 2 recepto, but it does bind to the high affinity receptor on activate t cells and prevents generation of signal 3

57
Q

Cytotoxic drugs to target alloantigen-specific T cells

A
  • These drugs kill all replicating cells by blocking DNA replication. Side effects on bone marrow, intestinal epithelium, hair follicles
  • Act on alloreactive T cells after they have been activated, so administered after transplant
58
Q

Hematopoietic stem cell (HSC) transplantation

A

Stem cells repopulate donor hematopoietic cell population

Used to treat genetic abnormalities and cancer

No shortage of donors, but close HLA matching required

Transplantation of HSC is much easier than organs

59
Q

T cell selection: Implications for successful bone marrow transplantation

A
  • Donor T cells undergo positive selection by recipient thymic epithelium resulting in restriction by recipient HLA
  • Later, in an immune response they will be presented with antigen by donor-derived HLA on DC
  • ** look at slide
60
Q

Graft vs. host disease (GVHD):

A
  • allogenic hematopoietic cell transplant contains mature and memory T cells
  • T cells circulate in blood to secondary lymphoid tissues. alloreactive cells interact with DC and proliferate
  • effector CD4 and CD8 enter inflammed tissuess by the conditioning regimen and cause further tissue damage
  • Mature T cells in the donor bone marrow attack host tissue in an alloreactive fashion
  • Proliferating tissues damaged by irradiation are in an inflamed state and are susceptible to GVHD. DC in these tissues are activated and migrate to draining lymph nodes. Alloreactive T cells enter inflammed tissues
  • Type IV hypersensitivity reaction
61
Q

Minor histocompatibility antigens can trigger GVHD

A
  • Even with a perfect HLA match, many patients eventually develop GVHD. Due to differences in minor histocompatibility Ag
  • Donor T cells can respond to alloantigen encoded on the Y chromosome (H-Y antigens)
  • In these cases, donor T cells respond to Y-derived peptides presented on recipient APC
62
Q

Minor histocompatibility differences arise from presentation of polymorphic self peptides to T cells

A
  • polymorphic self proteins that differ in aa sequence between individuals give rise to minor histocompatibility antigen differences between donor and recipient
  • mostly trigger CD8
63
Q

Graft versus leukemia (GVL) effect

A

Prognosis for patients receiving transplant from identical twin (no alloreactivity) do not do as well as those in which there is some degree of alloreactivity

Alloreactive T cells kill residual tumor cells (Graft versus leukemia effect)

This effect can be seen in responses to minor histocompatibility antigens

The phenomenon occurs because stem cells along with partially and fully differentiated hematopoietic cells transferred to recipient

Stem cells self renew. Differentiating cells do not, so GVL is transitory

64
Q

Haploidentical transplantation as a new strategy in bone marrow transplantation

A

In haploidentical transplantation one haplotype is shared

GVHD is minimized by stringently depleting T cells in donor bone marrow and anti-T cell antibody treatment after transplant

NK cells mediate graft versus leukemia (GVL) effects through haplotype-specific loss of negative signal delivered by MHC class I recognition

NK cell compartment is the first to reconstitute after transplantation

65
Q

Autoimmunity

A

Autoimmunity results from T cells or B cells (antibodies) that attack self. A failure in self-tolerance mechanisms

Becoming increasingly frequent in Westernized countries (hygiene hypothesis)

Strikingly more common in women, for unclear reasons

Autoimmunity leads to chronic disease. Never resolves, at best it is just kept under control

Pathogenesis (beginning of disease) of autoimmunity is very poorly understood

66
Q

Hemolytic anemia

A

-Erthrocytes bind anti erythrocyte auto ab and then

  • FcR expressing cell in the splen undergo phagocytosis and erythrocyte destruction
  • Complement fixation and CR1 expressing cells in the spleen undergo phago and erythrocyte destruction
  • Complement activation and intravascular hemolysis results in erythrocyte and lysis destruction
67
Q

Multiple Sclerosis

A

Immune attack of myelin sheath surrounding nerve cells causing demyelination

Characterized by scars (sclerae) that form in brain and spinal chord

Motor weakness, vision impairment, loss of muscle coordination, spasticity

Mediated by Th1 cells and activated macrophages. Protease and cytokines released by activated macrophages cause demyelination Involvement of autoantibodies that recognize myelin

Relatively frequent occurrence

68
Q

Failure in self tolerance mechanisms leads to autoimmune

A

Mechanisms of self tolerance

  • Negative selection of B cells in the bone marrow
  • expression of tissue specific proteins in the thymus so that they participate in negative selection of T cells (AIRE)
  • negative selection of T cells in the thymus
  • exclusion of lymphocytes from brain, eyes, testis
  • induction of anergy in autoreactiv e b and t cells that reach periphery
  • suppression of autoimmune responses by Treg
69
Q

Patients lacking the transcription factor AIRE develop a large array of autoimmune syndromes

A

AIRE (autoimmune regulator) induces expression of tissue-specific genes in thymus during negative selection of T cells

Absence of AIRE results in failure to deplete tissue-reactive CD4 and CD8 T cells

APECED patients (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy)

70
Q

Genetic defect in Treg leads to IPEX

A

IPEX: immune dysregulation, polyendocrinopathy, enteropathy and X-linked syndrome

A rare syndrome. Defective FOXP3 gene which is required for Treg function

X-Linked gene, so mainly seen in males

Poly-syndromic, including enteritis, type I diabetes, eczema

Increased Th17, increased eosinophils and IgE

Only treatment is bone marrow transplant, otherwise death occurs within one year

71
Q

HLA and autoimmunity

A
  • makes a strong genetic contribution
  • large scale genetic typing of unrelated individulas across mult haplotypes are required to pin point HLA loci
  • However, note that even for the B27/ankylosing spondylitis link, only 2% of people with B27 develop disease
  • Ankylosing spondylitis is an autoimmune inflammatory disease affecting the spine
  • Relative risk of 1 means there is no effect of the HLA allotype
72
Q

Linkage of autoimmunity to HLA argues that loss of T cell tolerance underlies disease

A

Most HLA associations are with MHC class II alleles indicating role for CD4 T cells in pathogenesis

During inflammation (Th1 type), IFN-g increases MHC class II expression most highly on thyroid cells, pancreatic b cells, astrocytes and microglia.

These cells are located within tissues often targeted in autoimmune disease. Raises the question of whether inflammation is a trigger for loss of tolerance

B cell autoimmune responses invariably involve class switched immunoglobulin. Loss of T cell tolerance likely underlies these responses, reflecting activation of circulating autoreactive B cells

73
Q

Autoantibody binding to receptors results in autoimmune pathology

A

Antibodies can act as agonists – chronically turn on response mediated by receptor
or as antagonists – binding to receptor and blocking the normal function of the ligand

74
Q

Graves disease

A
  • agonisitc Ab
  • iodine taken up by thyroid epeithelial cells and used to make thyroglobulin
  • VSH stimulates endocytosis of thyroglobulin and generation of t3 and T4
  • chronic overproduction of T3 and T4 causes heat intolerance and nervousness/irritability
  • anti TSH receptor Ab causes graves disease
  • Nervous system signals pituitary release of thyroid stimulating hormones (TSH) when increased energy required (e.g. temp drop)
  • TSH stimulates T3 and T4 release. Biologically active thyroid hormones. Increases metabolism and also shuts off pituitary TSH release
  • GD associated with HLA DR3. Implicates DR3 presentation of a peptide derived from TSH receptor
75
Q

Antagonistic autoantibodies - anti-acetylcholine receptor antibody in Myasthenia gravis

A
  • Ach receptors are internalized and degraded leading to impaired muscle contraction
  • Autoantibody causes receptor cross-linking, internalization and degradation
  • Myasthenia gravis and Graves’ disease are examples of tissue/organ specific autoimmunity
  • (Diabetes, which involves defective glucose uptake in all cells is an example of systemic autoimmunity)
76
Q

Intramolecular epitope spreading in pemphigus vulgaris

A
  • Pemphigus vulgaris: Blistering of skin caused by IgG Ab response to desmoglein
  • Desmoglein is an adhesion molecule involved in binding of skin keratinocytes to each other
  • Antibodies are first made to EC5, then during clinical disease to EC1 and EC2
  • EC5 is nonpathological IgG, EC2 and 1 are pathological
77
Q

Hypothesized pathogenesis of PV

A
  • IgG made against EC5 epitopes forms immune complexes with soluble forms of desmoglein
  • epitopes of EC5 are covered by IgG, epitopes of EC1 and 2 can engage B cell receptors
  • Ab made against epitopes at EC1 and2 unzip the adhesive interaction of desmoglein
  • Anti-EC5 antibodies are nonpathogenic because they cannot bind cell surface EC5 due to close proximity of cell membrane

Remember – the autoreactive B cells are initially triggered by autoreactive T cells

78
Q

Intermolecular epitope spreading: Systemic lupus erythematosus (SLE)

A

Systemic autoimmune disease involves autoantibodies to a broad and expanding range of cellular constituents (as SLE progresses)

Anti-nucleic acid and nucleosome antibodies are prominent

T cell responsive is broaden through T and B cell interactions and activation

79
Q

Rheumatoid arthritis is an autoimmune disease manifesting as inflammation in joints

A
  • Most RA patients have autoantibodies against Fc region of IgG
  • Deposit as immune complexes in joint tissues causing inflammation
  • Strong association with HLA-DR4 allotype
  • Also associated with responses to citrullinated peptides
  • PAD makes a positive arginine to a neutral one
  • Destabilizes proteins and increases degradation
  • creates novel B and T cells epitopes
80
Q

Does infection trigger autoimmunity?

A
  • hypothesis
  • tissue damage and inflammation can somehow lead to a loss of T cell tolerance
  • evidence in mouse models, only if co injected with inflammation inducing microbial compents and self antigens
  • Some associations: People with HLA-B27 undergoing food poisoning have greater risk of developing reactive arthritis compared to whole population of HLA-B27 individuals
81
Q

Infection, autoimmunity and Streptococcus:

A
  • Example of molecular mimicry
  • Rheumatic fever caused by Streptococcus pyogenes
  • Inflammation of heart, kidneys and joints following throat infection. Possible break in tolerance
  • Can lead to life threatening heart disease through host-directed complement activation
  • It’s transient because T cells do not recognize the autoantigen. T cell independent antibody response
  • Some ab cross react with heart tissue and cause rheumatic fever
82
Q

Type I Dieabeties

A
  • resembles type IV hypersensitivity
  • influx of lymphocytes in the pancreas marks destruction of B cells
  • insulin producing B cells are detroyed by autoreactive T cells (esp CD8)
83
Q

HLA genetics influence resistance or susceptibility to T1D

A
  • Heterozygous for DQ2 and DQ8 are most susceptible to type 1 diabetes
  • DQ2 and DQ3 allotypes individually predispose to T1D
  • When expressed together, susceptibility to T1D increases further
84
Q

Celiac disease

A
  • food hypersensitivity similar to autoimmunity
  • T cells respond to gluten peptides in wheat flour
  • Resulting inflammation causes villus atrophy, food malabsorption, diarrhea
  • Relatively common in Western Caucasian populations where bread is part of the diet
85
Q

Pathogenesis of Celiac disease

A

-gluten degraded into Proline rich fragment resistant to proteolytic degradation
-enters gut tissue and is deaminated which Generates an altered gluten peptide
(similar to modification of peptides in Rheumatoid arthritis)
-then Naive CD4 t cell responds to deaminated peptides presented by HLA-DQ
-DQ2 and DQ8 allotypes are associated with disease (same as in T1D)
-inflammatory effector T cells cause villous atrophy
-Destruction of epithelial cells presumably through presentation of modified gluten peptides
-Most people with DQ2 or DQ8 allotypes never develop Celiac disease, but people with the disease have higher frequency of these allotypes
-Other predisposing factors: Early childhood rotavirus infections, adult IFN-g therapy for hepatitis infection
-Existence of Celiac disease may indicates the relative novelty of bread in the diet (12,000 yrs)

86
Q

Autoinflammatory diseases

A

Do not involve antibodies or T cell effectors

Caused by defects in innate immune effectors – innate responses to self

Strong genetic associations

They are also increasing in incidence in the West

A current area of expanding knowledge as genomic studies and our knowledge of innate immunity have increased

87
Q

Genes and proteins linked to autoinflammatory diseases

A
  • TFN receptor 1 (CD120a)
  • NLRP3 (cryopyrin)
  • NOD 2
  • IL 10 receptor alpha and Beta

Immunology (4 decks)

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