Topic 5.3 - Immune mediated disease

immune mediated response (3)

associated with either too much or too little of an immune response

inappropriate → autoimmunity, hypersensitivity, graft rejection

too little → immunodeficiency

self tolerance - def

unresponsiveness of an individual’s lymphocytes to their own antigens

prevents self-reactive lymphocytes from causing harm

basis of autoimmune disease

breakdown of tolerance

mechanisms of tolerance - list (4)

1. clonal deletion

2. clonal anergy

3. clonal ignorance

4. regulation

mechanisms of tolerance - deletion (2)

self reactive lymphocytes die via apoptosis

tends to occur in primary lymphoid porgans or can be induced in peripheral system

mechanisms of tolerance - anergy (2)

silencing of self-reactive lymphocytes → unable to respond even if presented to

eg. TCR and MHC-antigen interactions but no CD80/CD86 on host cell

mechanisms of tolerance - ignorance

self-reactive lymphocytes don’t have opportunity to see/ respond to cognate antigen → remain in a naive state

mechanisms of tolerance - regulation (2)

active suppression of antigen-specific lymphocytes

mechanisms of tolerance - anergy benefits example

If T cell interacts with MHC-host antigen with TCR → no activation

presenting cell only upregulate B7 molecules if presenting pathogen

mechanisms of tolerance - clonal ignorance examples (2)

1. physical separation → antigens in immune privileged sites or are intracellular

2. low antigen concentrations/ affinity

location of tolerance for T cells (2)

thymus - central tolerance

peripheral tissue = peripheral tolerance

T cell central tolerance to peripheral antigens

autoimmune regulator (AIRE) = transcription factor that drives peripheral gene expression in the thymus

binds to promoter region of genes to stimulate expression of peripheral antigens

T cell peripheral tolerance - anergy summary

self-reactive T cell encounters self-antigen but co-stimulatory molecules not expressed → T cell becomes unresponsive

T cell peripheral tolerance - how is anergy reinforced for activated T cells (3)

CTLA-4 mediated inhibition

CTLA-4 expressed by activated T cells and competes with CD28 for B7 molecules

professional APCs upregulate B7 during infection/ inflammation so low B7 and CTLA4 inhibition reinforces tolerance

T cell peripheral tolerance - suppression summary

some reactive T cells in thyroid become regulatory T cells and inhibit activation of T cells that recognise same antigen in peripheral tissues

T cell peripheral tolerance - suppression (T regulatory cell features - 3)

T regs express CD25 and transcription factor FOXP3

inhibit T cell activation by secreting cytokines that dampen T cell response → IL-10 and TGF-beta

express CTLA-4 → compete with CD28 for B7

T cell peripheral tolerance - deletion summary (2)

T cells that recognise self antigens with high affinity or repeatedly stimulated by antigens may die by apoptosis

can be induced by two pathways → intrinsic or extrinsic

T cell peripheral tolerance - induction of deletion pathways (2)

intrinsic → imbalance between Bcl-2 family proteins

extrinsic → death receptor

B cell central tolerance location

bone marrow

difference between effectiveness of B cell and T cell tolerance (2)

deletion of self-reactive B cells not as important as that of self-reactive T cells → require stimualtion by CD4+ T cells to be activated

those recognising with high affinity will undergo apoptosis or receptor editing by gene rearrangement → unresponsive or weakly recognising will exit bone marrow

why do B cells with high affinity for self antigens need to be deleted

can be activated without CD4+ T cell activation via cross-linking

B cell peripheral tolerance

B cells that recognise self antigens in peripheral tissues become anergic or die by apoptosis→ may trigger inhibitory receptors that prevent activation

immune privileged organs - examples and reason

eye, brain, testes

inflammation in tissues could cause severe damage so immune cells prevented from entering to prevent antigen exposure

autoimmunity - def

immune response to self antigens through a breakdown of self tolerance

mechanisms of autoimmunity - list (3)

inheritance of susceptibility genes

environmental triggers promote activation fo self-reactive lymphocytes

emerging factors

mechanisms of autoimmunity - supporting evidence for inheritance of susceptibility genes (2)

Autoimmune diseases tend to run in families

affects monozygotic twins more than dizygotic twins

usually caused by multiple genes → polygeneic

mechanisms of autoimmunity - inheritance of susceptibility genes (2 examples)

HLA genes → highly polymorphic

genes associated with immune regulation and self tolerance

how are MHC genes associated with predisposition to autoimmunity

some HLA alleles occur wit greater frequency in people with autoimmune disease

polymorphism of HLA alleles = associated with AA in peptide binding cleft → presentation of antigen in clefts may increase or decrease immune recognition of self-peptides

non-HLA genes that can predispose to autoimmunity - examples (3)

apoptosis

inhibition of t cells → eg. CTLA-4

clearance of immune complexes and apoptotic bodies → eg. via macrophages

how can changes to tissue act as environmental triggers that promote autoimmunity (4)

1. inflammation → cytokines may activate anergic autoreactive bystander cells via co-stimulatory molecules

2. tissue injury → tissue antigens may be altered by injury or cryptic epitopes exposed

3. molecular mimicry → microbial antigens share amino acid sequence with host protein

4. drugs and toxins → can bind self antigens and modify them to form new antigens recognised as foreign to immune system

mechanisms of autoimmunity - emerging factors (3)

microbiome → non-pathogenic microorganisms that colonize the gut and skin affect the relative proportions of effector and regulatory T cells

gender → many autoimmune diseases are more prevalent in women than men

epitope spreading → injury caused by initial autoimmune response exposes previously concealed self antigens

autoimmunity always leads to autoimmune disease

not all autoimmunity will lead to autoimmune disease

experimental models of autoreactivity often need triggering events to develop disease

evidence supporting not all autoimmunity leads to autoimmune disease (2)

transient anti-nuclear antibodies produced after viral infection have no outcome in most cases

increase in incidence of autoantibodies with increasing age but most show no evidence of autoimmunity

autoimmune diseases occurs when…

inappropriate immune response causes an injury that affects structure/ function of cells/ tissues/ organs

criteria for autoimmune disease (3)

1. presence of immune reaction specific for some self antigen or self tissue

2. evidence that such immune response is causing the damaged tissue and is not simply responding to it

3. absence of another well-defined cause of disease

criteria for autoimmune disease - rheumatoid arthritis example

criterion 1

chronic autoimmune systemic inflammatory disease characterised by presence of inflammation in joints and presence of antibodies that target host antigens (eg. citrullinated peptide)

criteria for autoimmune disease - repetitive strain injury example

criterion 2 not met

often a more chronic condition which develop over time due to excessive forces through hand and wrist -> pain, aching and or tenderness is associated with RSI not an autoimmune disease

criteria for autoimmune disease - osteoarthritis example

criterion 1 not met

associated with joint pain and swelling but unlike rheumatoid arthritis, is not associated with presence of immune reaction specific for some self antigen or self tissue

features of autoimmune diseases (2)

usually chronic and progressive

autoimmune diseases - classification by location (2)

organ specific or systemic

organ specific autoimmune diseases - summary

confined to particular organ or cell types

systemic autoimmune diseases - summary

multiple organs and systems → generally available antigens

organ specific autoimmune diseases - examples and antigens targeted (6)

Type I diabetes -> beta islet cell destruction and absolute deficiency of insulin

Autoimmune haemolytic anaemia -> target antigens on RBCs

Rheumatic heart disease -> antigen in heart

Myasthenia gravis -> usually associated with autoantibodies targeting acetylcholine receptors

Graves disease -> production of autoantibodies against multiple thyroid proteins

Multiple sclerosis -> specific antigen in white matter of brain

systemic autoimmune diseases - examples and antigens targeted (3)

Systemic Lupus erythematous (SLE) -> antinuclear antibodies target nuclear antigens (present throughout body) -> injury caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues

Pan systemic sclerosis

Rheumatoid arthritis -> affects joints, but antigen targeted is generally available

immune deficiency - summary

immune mediated injury with too little activation of B and T cells

results in increased susceptibility to infection and predisposition to some cancers

immune deficiency - features (4)

can be genetically determined or acquired

can be recurrent/ overwhelming infection → unable to fend against pathogens

increased incidence of opportunistic infection

can predispose to cancer

types of immune deficiency (2)

primary → caused by inherited defect in immune system → can affect innate host defences or adaptive immunity

secondary → acquired by declining or suppressed immune system

primary immune deficiency - defects in early innate response sumamry

typically affect leukocyte functions or complement system

primary immune deficiency - defects in adaptive immunity summary

affect B and T cell development and cause immunodeficiencies from abnormalities in lymphocyte maturation or activation

primary immune deficiency - example defects affecting early innate response (6)

• Mutation in TLR -> ability to recognise PAMP

• Leukocyte adhesion (eg. ligand for selectins) -> failure of leukocyte adhesion and recruitment

• Mutation in genes encoding formation of phagosome affecting fusion of phagosome with lysosome

• Mutation in genes that encode phagocyte oxidase affecting function of microbial killing

• Complement component C3 mutation inhibiting both classical and alternative complement pathways

• Mannose-binding lectin mutation preventing activation of lectin pathway of complement activation

primary immune deficiency - example defects affecting adaptive immunity (5)

• Mutation in common subunit of cytokine receptors -> prevents cytokine signalling

• Mutation affecting thymus development -> T cell development

• Mutations affecting MHC-II expression -> development of CD4+ T cells and thus B cell function resulting in combined immunodeficiency

• Mutation impairing isotype switching to produce IgA-producing plasma cells

• Mutations resulting in hypogammaglobulinemia -> low Ig levels

secondary immune deficiency - declining or suppressed immune system in response to… (5)

age

malnutrition

diseases such as diabetes and cancer

latrogenic immunosuppression in response to medical treatment for cancer or drugs used to prevent rejection of transpant

immunosuppression in response to infection of cells of immune response

most serious secondary immunodeficiency

acquired immune deficiency syndrome caused by infection with human immunodeficiency virus

AIDS - HIV summary

retrovirus from lentivirus family that integrates into host cell’s genome during lifecycle

invades through mucosal epithelial via sexual contact, inoculation with ifnected blood or blood products and from mother to child

AIDS - tropism of HIV-1

infects CD4+ T cells, macrophages and dendritic cells

AIDS - HIV pathogenesis (2)

Destruction of CD4+ T cells by direct viral infection causing apoptosis, cell lysis or interfering with protein synthesis, or through action of host CD8+ T cells that recognise virally infected cell

Lost cells replaced but eventually CD4+ cell numbers decline and patient develops life-threatening opportunistic infections

AIDS = HIV diagnosis (2)

diagnosed through presence of virus specific antibodies and eventually declining CD4 cell numbers

viral load and number of CD4+ T cells = clinically useful predictors of progression of disease

AIDS - treatment of HIV-1 infection (3)

without treatment, infection is fatal

treat with antiretroviral therapy (ART) which can reduce plasma viral RNA to undetetctable levels in most treated patients for years

treatment is lifelong and cure and vaccine yet to be developed

AIDS - complications of HIV infection and development of AIDS

infection is clinically silent (asymptomatic) as virus load is contained and lost CD4+ T cells are replaced by progenitor cells → CD4+ T cell numbers will decline without treatment as viral load increases, leading to immune deficiency

AIDS develops with patient increasingly susceptible to opportunistic infections

AIDs - examples of increased susceptibility to infection and predisposition to some cancers (4)

neoplasms

cachexia

kidney failure

CNS disease (HIV-associated neurocognitive disorder or HAND)

need for organ transplantation arises from… (3)

• Born with structural abnormality of an organ

• Bron with a disease that causes an organ to fail

• Develop a disease or illness that causes organ to fail

graft types (4)

• Allograft = same species

• Autograft = recipient

• Isograft = recipient's identical twin

• Xenograft = between species

what donations are typically isografts (2)

blood and skin

major barrier to transplantation of organs between individuals of same species

immunological rejection of transplanted tissue

mediated by histocompatibility molecules, not organ specific proteins

barrier to successful transplantation - impact of MHC molecules

MHC = polymorphic so no two individuals are likely o express the same set of MHC molecules except identical twins

HLA gene products = co-dominantly expressed → thousands of copies of MHC molecules expressed per cell

types of immune recognition of allografts (2)

direct or indirect → influences type of immune response mounted by recipient and form of tissue damage

direct immune recognition of allographs - summary

host T cell activated by donor APC expressing donor MHC-I and MHC-II

direct immune recognition of allographs - steps (3)

1. Donor APC expresses donor MHC-I and MHC-II and migrates to local lymph node to stimulate alloreactive recipient T cells

2. Recipient CD4+ T cells recognise donor MHC-II as foreign and become activated -> produce cytokines that damage grafts by cytokine-mediated inflammation

3. CD8+ T cells recognise donor MHC-I as foreign and become activated -> recognise and kill graft cells expressing MHC-I

direct immune recognition of allographs - summary

host CD4+ T cells recognise donor MHC and proteins as foreign when they are processed and presented by host APCs
(humoral response)

direct immune recognition of allographs - steps (3)

1. Recipient APCs phagocytose donor tissue and presents allogeneic MHC fragment to recipient CD4+ T cells

2. Alloreactive CD4+ T cells recognises donor MHC presented by recipient APCs and becomes activated -> produces cytokines

3. Activated alloreactive CD4+ T cells activate recipient B cells -> clonal selection and expansion to produce antibody producing plasma cells

evidence of immune mediated graft rejection in mice (3)

• Skin grafts from mouse strain A onto mouse of same strain is tolerated

• Skin grafts from mouse strain A onto mouse strain B is tolerated within the first 7 days of transplants but rejection occurs 10-14 days after transplantation

• Following rejection of mouse strain A graft by mouse strain B, a second graft from mouse strain A is rapidly rejected within 2-7 days

  • Graft shows accelerated rejection

mechanisms of graft rejection (2)

T cell mediated → T cell cytokines and CD8+ T cells

B cell mediated → alloantibodies, complement, neutrophils, NK and macrophages

T cell mediated graft rejection - steps (4)

1. Donor or recipient macrophages present alloantigens to recipient CD4+ T cells

2. Activated T cells secrete cytokines that promote interstitial inflammation and tissue necrosis in parenchyma and endotheliosis and thrombosis in blood vessels

3. Alloreactive CD8+ T cells generated by direct graft recognition recognise MHC-I expressed on parenchymal and endothelial cells and directly kill them

4. Endotheliosis and thrombosis + damaged endothelium

B cell mediated graft rejection - steps (3)

1. Alloreactive B cells recognise and produce alloantibodies to both class I and class II MHC donor proteins

2. Alloantibodies encounter donor MHC-I and II in blood vessels and activate complement, neutrophils, NK cells, and macrophages

3. Alloantibodies cause graft rejection in vascular system -> involves intravascular thrombosis and endothelial cell necrosis

classification of graft rejection - list (3)

reflects mechanism of immune mediated graft rejection

1. hyperacute → minutes to hours

2. acute → days to weeks

3. chronic → months to years

classification of graft rejection - hyperacute (3)

presence of pre-existing antibodies in recipient’s circulation

very rare as every donor and recipient is matched for blood type and potential recipients are tested for antibodies against cells of prospective donor

pre-existing alloantibodies to MHC and ABO antigens arise in recipients who have had a blood transfusion, previous organ transplant or previous pregnancy

classification of graft rejection - acute (4)

can be T or B cell mediated

cellular graft rejection by parenchymal damage = CD8+ T cells destroy graft cells and or CD4+ T cells secrete cytokines and induce inflammation which damages graft

cellular graft rejection by vascular damage = T cells may cause damage

humoral graft rejection = alloantibodis bind to vascular endothelium and activate complement and induce inflammation

classification of graft rejection - chronic (2)

believed to be T cell mediated

results in interstitial fibrosis and gradual narrowing of graft blood vessels → arteriosclerosis

how can graft survival be improved (3)

1. considerations on transplant type → if transplants can be delayed for improved HLA matching or if anatomical capacity is important

2. pre-transplant assessment to evaluate the organ before transplant → HLA matching for compatible HLA types and cross-matching for presence of pre-existing antibodies in recipient’s sera that could cross-react with donor’s antigens

3. post-transplant immunosuppression → prevent rejection in transplants not between identical twins

impact of global immunosuppression and alternative to it

can result in too little immune response and increase risk of opportunistic infections and neoplasms

alternative = induce donor-specific tolerance in host cells

targets of immunosuppression therapy (6)

Inhibitors of t cell signalling → Eg. cyclosporine and tacrolimus

Inhibitors of proliferation → Eg. rapamycin, mycophenolate, azathioprine

Anti-lymphocyte antibodies → Eg. anti CD3, anti IL-2r, anti CD52

Co-stimulation antagonists → Eg. block B7 binding to CD28

Drugs targeting antibody responses → Eg. IVIg, anti CD20 (rituximab)

Anti-inflammatory → Eg. corticosteroids -> reduce MHC expression

hypersensitivity reactions - cause

caused by immune-mediated injury → imbalance between effector and control mechanisms of immune response resulting in excessive, poorly controlled or misdirected response

antigens pathogenic immune response can be directed against (3)

1. host’s own antigens → damage to host tissue and organs by effector functions of T and B cells that recognise self-antigens (autoimmune disease)

2. microbe → excessive or persistent microbe causing inflammation and tissue damage

3. environmental → non-infectious and harmless antigens

reasons why hypersensitivity is difficult to treat

stimuli is difficult/ impossible to avoid or eliminate

response is exacerbated by immune systems which has positive feedback loops an amplification mechanisms to ensure defeat of perceived invading thread

leads to chronic conditions

classification of hypersensitivity reactions - list (4)

based on antibody and cell-mediatory effector mechanisms

Type I = immediate

• IgE specific for environmental antigens

Type II = antibody mediated

• IgG and IgM antibodies directed to cell surface or ECM antigens

Type III = immune complex-mediated

• Circulating IgG and IgM form complexes with antigens and cause disease when deposited in tissues of the body

Type IV = T cell mediated

• CD4 an CD8 T cells and macrophages

Type 1 hypersensitivity - summary

Inappropriate (pathological) triggering of a defensive immune response normally (physiological) directed to helminths

type 1 hypersensitivity - role of Th2

Th2 CD4+ T cells secrete:

• Il-4 to induce switching to IgE which binds to mast cells

• IL-5 to recruit and activate eosinophils

• IL-13 to act on epithelial cells and stimulate mucous secretion

factors affecting development of type 1 hypersensitivity (2)

1. genetic factors

• Atopic individuals appear to have polymorphisms in genes such as those encoding Th2 induced cytokines and some HLA alleles

1. environmental

• hygiene hypothesis and underdevelopment of T reg cells that moderate Th2 response

• can affect integrity of mucosal barrier and increase risk of developing allergies

type 1 hypersensitivity - pathogenesis (6)

1. Allergens is inhaled, ingested, injected or comes in contact with skin

2. Allergens cross mucosal barrier and are taken up by sub-epithelial APCs

3. APC present antigen to naïve Th cells -> produce that lead to development of Th2 cells

4. Th2 cells stimulate B cell activation and IgE production via IL-4

5. IgE binds with high affinity to IgE receptors found on surface of mast cells in tissues and basophils in circulation

   • Mast cells have preformed granules containing histamine, proteases, and chemotactic factors

6. Allergen reaction when IgE bound to mast cells is cross-linked by an allergen

type 1 hypersensitivity - effect of granules released (immediate and late phase responses)

Contents of their granules and chemicals derived from membrane phospholipids released → membrane phospholipid-derived chemicals include platelet-activating factor and arachidonic aid metabolites

Immediate immune response -> vasodilation, vascular leakage, smooth muscle spasm -> mucous production, airway congestion, vomiting, diarrhoea

Late phase via cytokines and chemokines -> attract leukocytes such as eosinophils and cause epithelial damage and bronchospasm

Type 2 hypersensitivity - summary

antibody-mediated diseases → IgM and IgG directed against tissue antigens

Type 2 hypersensitivity - antigen types (2)

Endogenous -> host antigens

Endogenous antigens that has been modified by an exogenous source -> chemical or microorganism

type 2 hypersensitivity mechanisms of cell death and tissue damage (3)

1. Opsonization and phagocytosis

• via complement activation: C3a and C5 also induce inflammation and can lead to membrane attack complex → directly damage cell by osmotic lysis

• via IgG → antibody-dependent cellular cytoxicity where Nk cells and macrophages directly lyse cells coated with IgG

2. Inflammation

• binding of antibodies to host tissues stimualtes release of cytokines → recruit leukocytes that release lysosomal enzymes and ROS to cause tissue damage

3. Cellular dysfunction

• binding of IgG and IgM to self-antigens can interfere with normal function by blocking or changing function of antigen bound to

type 3 hypersensitivity - summary (2)

inadequate clearing of immune complexes formed between antibody and antigens

under normal circumstances, immune complexes form in circulation and lead to activation of complement which is recognised by complement receptors on surface of RBC → transport complexes to liver and spleen to be removed

type 3 hypersensitivity - pathogenesis steps (3)

1. Inadequately cleared immune complexes

2. deposited in blood vessels or tissues where blood is filtered

3. induce inflammatory reactions that cause tissue damage via opsonisation and phagocytosis

type 3 hypersensitivity - cause of immune complexes inadequately cleared (4)

• present in large amounts

• intermediate in size

• antigen is in excess

• fewer F’c receptors available to facilitate removal

type 3 hypersensitivity - methods of tissue damage via inflammation (3)

Complement activation → Increased vascular permeability + attract and activate neutrophils and monocytes

Activated neutrophils and monocytes → phagocytosis + secretion of pro-inflammatory substances, enzymes, ROS

Platelet activation via endothelial cell damage → microthrombi (blood clots) cause local ischemia to tissue being supplied by that blood vessel

principal morphologic manifestations of immune complex injury

acute vasculitis (inflammation of blood vessels) associated with fibrinoid necrosis of vessel wall and intense neutrophilic infiltration

type 3 hypersensitivity - glomerulonephritis

inflammation caused by immune complexes forming in glomerulus of kidney→ blood filtered at high pressure to form urine

type 3 hypersensitivity - rheumatoid arthritis

inflammation caused by immune complexes forming in joints → blood filtered at high pressure to form synovial fluid