immunology

  • Cytokines made by macrophages

     

    IL-1

    • Costimulator of TH2 cells

    • Stimulates acute phase response

     

    IL-6

    • Promotes B cell differentiation

    • Stimulates acute phase response

     

    IL-12

    • Costimulator of TH1 cells

     

    IL-18

    • Promotes IFN-y production by TH1 cells

     

    TNF-a

    • Cytotoxic

    • Stimulates T cell growth

    • Stimulates acute phase response

    • Triggers inflammation

     

     

     

    What are the proinflammatory cytokines

    • IL-1b

    • IL-6

    • TNF-a

     

     

     

     

    CD8

    • Kill virus infected cells

    • Target viruses and intracellular bacteria

     

    TH1 CD4

    • Activate infected macrophages

    • Help B cells produce antibodies

    • Target microbes in macrophage vesicles and extracellular bacteria

     

    TH2 CD4

    • Help B cell produce antibodies

    • Help antibody switching to IgE

    • Targets helminths

     

    TH17 CD4

    • Enhance neutrophil response

    • Promote barrier integrity

    • Target fungi

     

    TFH

    • Antibody production

    • Isotype switching

    • Target all types

     

    T Reg CD4

    • Suppress T cell responses

     

     

    5 important cytokines

     

     

    IL-1 beta

     

    Local

    • Activates vascular endothelium (leaky, adhesion molecules, cytokines)

    • Activates lymphocytes

    • Activates local tissue destruction

    • Increases access of effector cells

     

    Systemic

    • Fever

    • Production of IL-6

     

    IL-6

     

    Local

    • Lymphocyte activation

    • Antibody production

     

    Systemic

    • Fever

    • Acute phase protein production

     

    TNF-a

     

    Local

    • Activates vascular endothelium

    • Increases vascular permiability

    • Increases entry of IgG, complement and cells to tissue

    • Fluid drainage to lymph nodes

     

    Systemic

    • Fever

    • Mobilisation of metabolites

    • Shock

     

     

    CXCL8

     

    Local

    • Chemotactic factors recruit neutrophils, basophils and T cells to site of inflammation

     

    IL-12

     

    Local

    • Activates NK cells

    • Induces differentiation of CD4 T cells into TH1 cells

     

     

    Lectin Pathway

    • Mannose binding lectin and ficolin's bind to carbohydrates on pathogen surface

    • Complement proteins assemble together to make C3 convertase

     

    Classical

    • C1q component interacts with pathogen surface or antibodies from adaptive immunity that are bound to the surface of the pathogen

    • Complement proteins assemble on the surface of pathogen or in an infected cell to make C3 convertase

     

    Alternative

    • C3 undergoes spontaneous hydrolysis at low levels in the body

    • Deposition of enzyme C3 convertase on microbial surface

    • If no infection, no deposition of enzyme on surface of pathogen

    • Production of C3 convertase

     

    C3 convertase cleaves C3 molecule of complement into C3a and C3 b

     

    • C3b deposits itself on the surface of pathogen/cells

    • C3a is released

     

    Steps of leukocyte migration

     

    • Interactions between activated vascular endothelium and molecules on leukocyte

     

    1. Rolling adhesion

    2. Tight binding: caused by cytokines and chemokines

    3. Diapedesis: crossing of cell wall

    4. Migration: follows gradient of cytokines/chemokines

     

     

    Phagocytic cells

    • Neutrophils and macrophages

    • Attracted to site of infection by dead/dying cells

     

     

    Phagocytosis steps

     

    1. Chemotaxis

    2. Adherence

    3. ingestion

    4. Destruction

     

    Fever

     

     

    1. Microbial components engage PAMPs on macrophages

    2. Release inflammatory cytokines

    • IL1

    • IL6

    • TNFa

    1. These cytokines especially IL-1 act on hypothalamus and increase body temperature

    2. Systemic outcome of fever

     

     

    Inflammatory response can be localised or systemic

     

    IL-1

    • Acts on brain causing fever, anorexia, somnolence

    • Reduce energy consumption

     

    IL-6

    • Acts on liver

    • Release of acute phase proteins = recognition and destruction of invading pathogen

    • Acute phase protein = c reactive protein

    • Elevated CRP = inflammation

    Cytokines

    • Cell to cell communication

    • Immunoregulating/modulating agents

    • Interleukins and interferons

    • Can effect brain and liver and lead to acute phase response

     

    Acute phase proteins

     

    1. Bacteria induce macrophages to produce IL-6

    2. IL-6 acts on hepatocytes in liver to induce synthesis of acute phase proteins

     

    C reactive proteins

    • Binds phosphocholine on bacterial surfaces

    • Acts as an opsonin: coats bacteria and enhances uptake of bacterium by phagocytes

    • Can also help activate complement

     

    Mannose binding lectin

    • Bind to carbs on surface of bacteria

    • Acts as opsonin increasing uptake by phagocytes

    • Initiate lectin pathway

     

     

    Acute inflammation

    • Happens quickly

    • Major cell type is neutrophils, followed by monocytes - > macrophages

    • Redness (vasodilation), swelling (plasma proteins and fluid in tissue, vascular leakage, histamines, leukocytes), pain (kinins), heat (blood flow)

     

    Chronic

    • Lasts longer

    • Leukocytes, plasma cells (different cell types)

    • Granuloma: collection of immune cells formed when immune system is walling off but cannot eliminate foreign object

    • Tissue destruction due to high numbers of inflammatory cells

     

     

     

    Consequences of activated complement system

     

    1.  

    • C3a and C5a act as chemotaxins

    • Recruit phagocytic cells to site of infection

    • Promote inflammation

     

    1.  

    • phagocytes that have receptors for C3b can help engulf and destroy the pathogen

    • Phagocytes recognize c3b on surface of pathogens, can engulf and destroy it

     

    1.  

    • Formation of membrane attack complex (MAC) = pore formation in the microbe or in infected cell

    • Disrupts cell membrane and leads to lysis

     

     

     

    Chemotactic factors that attract neutrophils

    1. Complement factors

    2. Prostaglandins

    3. Kinins

     

     

    Steps of phagocyte migration

     

    1. Margination

    2. Rolling

    3. Tight adhesion

    4. Diapedesis (cell crosses blood vessel wall)

     

     

     

     

    B cells and macrophages present antigens to sensitized helper T cells

    Dendritic cells present antigen to naïve helper T cells

     

    T cells and APC's (DC's) paracortex

     

    B cells follicles

     

     

     

    GALT = Immune

    • Secretory antibody IgA

    • Cell mediated immunity

    • T cells

    • Dendritic cells, macrophages and NK cells

     

    Inductive sites

    • Sites where antigens are processed and immune responses initiated

    • Peyer's patches, tonsils, NALT

     

    Effector sites

    • Antibodies and cell mediated responses are generated

    • Lymphoid nodules, lymphocytes: plasma cells

     

    IgA dominant immunoglobulin isotype at mucosal surfaces

     

     

    Called common mucosal immune system

    • MALT can be local, systemic or can get response from other mucosal tissue

    • Priming of lymphocytes at 1 MALT -> protective immunity at another MALT

     

    Adhesion molecules and chemokines bring immune cells

     

     

    Peyer's patch

    • Mostly secondary lymphoid tissue

    • Induction of adaptive immunity

     

    Peyer's patch has…

    • Subepithelial dome

    • Follicles with B cells

    • T cells in between

     

     

     

    How do bacteria manipulate or escape host immune response

     

    1. Escape epithelial defences

    • Degrade mucous/physical barrier

    • Make enzymes that degrade antibodies

    • Antigenic variation: change surface antigens to become unrecognisable to host immune system

    • Changes in LPS, changes to pili, flagella

    • Polysaccharide capsules (coat of sugars around bacterial cells)

     

    1. Escape phagocytes and innate immunity

    • Capsules reduce antibody binding and opsonisation

    • interfere with phagocytosis

    • Interfere with phagocyte recruitment (degrade chemokines)

    • Kill leukocytes

     

    1. Evade adaptive immunity

    • Resistance to antibodies, don't bind as well to polysaccharide capsules

    • interfering with cytokines secretions

    • Interfere with antigen presentation

    • Inhibit B and T cell functions

     

     

    Virulence factors

    • Motility = Flagella, cilia, fimbriae

    • Compete for resources like iron

    • More resistant and more invasive

     

    How do they resist phagocytosis

    • Capsules

    • Protein A soaks up antibody

    • Fibrin clot formation

    • Prevent phagosome from acidifying and is protected inside

    • Kill or escape phagocytosis

     

    How do they evade adaptive

    • Capsules

    • Antigenic variation

    • Proteases

    • Myobacteria cause release of immune suppressive cytokine

    • Interfere with antigen processing and presentation

     

     

     

     

    Direct host damage

    • Exotoxins

    • Endotoxins

    • Killing host cells

     

    Indirect host damage

    • Cause immune complexes that cause inflammation/tissue damage

    • Molecular mimicry = autoimmunity

    • Aberrant immune response causes damage to own host

     

     

    Most important protective mechanisms against bacteria

    1. Complement

    2. PAMPs recognised by TLRs

    3. Phagocytes

    4. Antibodies and T cells

     

     

    Interstitial space like blood and lymph

    • Antibodies

    • Complement

    • Phagocytes

     

    Epithelial

    • Antibodies

     

    Intracellular

    • T cells and NK

     

    Intracellular in vesicles

    • Macrophages very important

     

     

     

     

    T cells need to receive multiple signals from APC before they can be activated and differentiate into effector and memory populations

    • Costimulation or antigen

     

     

    T helper cells drive inflammatory response

    • Helper other cells by producing cytokines

    • Help B cells be activated into plasma cells and produce specific antibodies

    • Help CD8 T cells activate to cytotoxic T lymphocytes

    • Activate macrophages to enhance phagocytosis and enhanced killing ability

    • Depends on cytokines released from APC's

     

     

     

    TH1 cytokines

    • IL2

    • IFN-Y

    • TNF-a

     

    • Inflammatory response

    • Respond to viruses and intracellular pathogens

    • Allograph rejection

    • Ig switching

     

    TH2 cytokines

    • IL-4

    • IL-5

    • IL-13

    • IL-10

     

    • Humoral B cell responses: class switching to IgE

    • Helminth Immunity

    • Allergy

    • Activate mast cells and eosinophils

     

     

     

    Cytotoxic T cells

    • Kill site infected with intracellular bacteria, viruses and tumours

    • Intrinsic pathway = Injects enzymes (granzymes and perforins) and cause death, apoptosis

    • Extrinsic = CD95 L, interaction outside cell = apoptosis

     

     

    Function of antibodies

    • Enhance phagocytosis via opsonisation (taken up easier)

    • Enhance classical pathways of complement mediate killing  initiated by antibodies = Classical pathway

    • Neutralize microorganisms and toxins

    • Prevent pathogen attachment

    • Antibody dependent cellular cytotoxicity

     

     

     

    3 main types of fungal infections

     

    1. Primary infections on skin and other surfaces

    2. Primary infections by dimorphic fungi: respiration

    3. Secondary infection by opportunistic fungi: temporary immunodeficiency

     

    • Once established fungi destroy TH1 cells

    • Type 4 hypersensitivity to fungal infections

     

     

     

    Acute

    • Rapid onset of disease with symptoms

    • Small incubation period

    • Cytopathic

    • Self limiting

     

    Examples of acute

    • Influenza

    • Smallpox

    • SARS

     

    Chronic

    • Long incubation period

    • No immediate cell death so mostly non-cytopathic

    • Virus is not cleared by immune system: high amount of virions remain

    • Persists in host for long period of time

    • Eventually symptoms appear

     

    Examples of chronic

    • Hepatitis B and C

     

    Latent infection

    • Begins like acute infection

    • Later there is latency: no virion production, no shedding of virus and no symptoms

    • Virus can reactive with stress, illness

    • Episodic reactivation: more virus is produced and symptoms occur

    • Cytopathic when reactivated

    • Do not always have symptoms

     

    Examples of latent

    • Shingles and herpes

     

    Slow- initial infection appears acute

    • Infection is largely cleared but low levels of virus remain

    • Can ultimately defeat the host

    • Often target immune system specifically

     

    Examples of slow

    • HIV

     

     

     

     

    NK cells and interferons important for defending against virus

     

     

     

    • Interferons = family of cytokines that inhibit viral growth

    • Recognise viral nucleic acids by cytoplasmic and membrane sensor proteins = PRR's

    • Inhibit transcription and translation of viral proteins

    • Adaptive immunity = Increase expression of MHC molecules on surface of cells and enhances antigen presentation

     

     

     

     

    IFN-a = type 1 interferon

    • Produced by virus infected leukocytes

     

    IFN-b = type 1 interferon

    • Produced by virus infected fibroblasts and epithelial cells

     

    IFN-Y = type 2 interferon

    • Released only by antigen stimulated T cells (mostly TH1 and NK cells)

     

     

     

    NK cells

    • Kill infected abnormal/stressed using cytotoxic granules

    • Activated based on lack of MHC

    • MHC molecules on normal cells recognised by inhibiting receptors

    • Cytotoxicity of NK cells is stimulated by type 1 interferons (a and B)

     

    Viruses can downregulate MHC 1 on surfaces of infected cells

    • Evades killing by cytotoxic T cells

    • Increases NK cell killing

     

     

     

    CD4 TH1

    • Cells activate macrophages enabling them to destroy intracellular microorganisms

    • Help CD8 cells

    • Help B cells switch antibodies from IgM to IgG

     

    CD4 TH2

    • Activate B cells to produce different Ig isotypes

     

     

     

     

    Antigenic drift

    • Mutations alter epitopes in haemagglutinin so antibody no longer binds

     

    Antigenic shift

    • RNA segments exchanged between 2 viruses

    • Occurs in secondary host

    • No cross protective immunity because it creates a new haemagglutinin

     

     

    Protozoa

     

    Innate

    • Phagocytosis and complement

     

    TH2 = Extracellular 

    • Antibodies, Mast cells, eosinophils

     

    TH1 = intracellular

    • Cytotoxic T lymphocytes

    • Macrophages activated by IFN-Y

     

     

    Immune evasion strats of protozoa

    • Antigenic variation

    • Intracellular localisation

     

    • Some protozoa can hide in RBC's which don't have MHC molecules so cannot be killed by cytotoxic T cells

     

     

    Protozoa can lead to hypersensitivity

     

    Type 1 (allergic)

    • Local irritation and inflammation involving mast cells and eosinophils

     

    Type 2 (cytotoxic reactions)

    • Immune destruction of RBC's = anaemia with babesia

     

    Type 3 (immune complex deposition)

    • Vasculitis, glomerulonephritis = leishmanias

     

    Type 4 (delayed type hypersensitivity)

    • Granulomas

     

    Autoimmunity

    • Immune responses against self = Trypasnomes

     

     

     

     

    Immune strategies of Helminth

     

    1. Thick cuticle: cannot be penetrated by complement, T cells and enzymes

    2. Different immune profile

    3. Cytokines often dampened

     

     

    Type 2 immunity

    • Roundworms, cestodes and trematodes

    • CD4 TH2 cell is major player = produces range of cytokines

    • IL-4 is major, IL-5 and IL13

     

     

     

    CD4 TH2 is major player in Type 2 Helminth Immunity = secretes IL-4 (IL-5 and IL-13)

     

     

    1. Helminth Infection

    2. IL-4 release

    3. TH2 cells secrete other cytokines IL-4, IL-5, IL-10 (immunosuppressive blocking IL-12)

    4. The secretion of IL-4 induces IgE and some IgG

    5. Expanded populations of Eosinophils, Mast cells, basophils and alternatively activated macrophages (wound repair)

     

     

     

     

     

    Cytokines released by TH2

     

    IL-13

    • Epithelial cell repair = Increased cell turnover: shedding of parasitized cells

    • Goblet cell release more mucous = lack of adherence to GIT = loss of parasite

    • Increase smooth muscle contraction enhancing worm expulsion

     

    IL-4 and IL-13

    • Recruit and activate M2 macrophages

    • Increase smooth muscle contraction

    • Tissue repair

     

    IL-5

    • Acts on eosinophils

    • Eosinophils Kill helminth parasites

    • ADCC of parasites if They have IgE

    • Enzymes and toxic elements

     

    IL-3 and IL-9

    • Arms Mast cells against helminth

    • Mast cells produce histamine and TNF-a when bound to IgE

    • Recruit inflammatory cells and remodel mucosa

     

    Mast cells have receptors that bind to IgE

    • When allergen or antihelminth binds it degranulates: histamine, heparin, proteases, IL-4 and IL-5

    • Mast cells and eosinophils involved in antihelminth

     

    Mast cell bound IgE (sensitized mast cell) triggers degranulation when bound to helminth antigens

    • Release products

    • Smooth muscle contraction

    • Increase vascular permeability

    • Epithelial cell turnover

     

    Eosinophils

    • Make products that damage helminth cuticles

    • Make many different molecules that can damage and penetrate (ROS, phospholipases)

    • How do they make ADCC = IL-4 class switching to IgE, eosinophils' receptors are engaged

     

     

    2 different mechanisms of expulsion of intestinal nematodes

     

    1. Mast cell dependent

    • Mast cell degranulation

    • inflammation

    • Increase permeability and fluid secretion

     

    1. Mast cell independent

    • TH2 response releases IL-4 and IL-13

    • goblet cells proliferate and Increase in mucous

    • Smooth muscle contractions

     

     

    TH2 Often decline during chronic helminth infections = increase in regulatory cells (T-reg)

    • Expand numbers of T-reg = asymptomatic tolerance

     

     

    1. Shedding of surface antigens

    2. Protease production to neutralise anti parasite immunity and degrade Ig

    3. Adsorbing host antigens and masking parasite antigens

    4. Regulation of host functions

    • Suppress neutrophils and macrophages

    • Suppress TH response

    • Neutralise respiratory burst and antioxidants

    • Use of cytokines as growth factors

     

     

     

     

     

    Hypersensitivity

     

    1. Sensitisation phase

    • First response to antigen

     

    1. Re exposure phase

     

     

     

     

     

    Type 1 Immediate hypersensitivity

     

    • Happens within minutes

    • Localised or systemic

    • Allergy and anaphylaxis

    • Allergens generally encountered on mucosal surfaces

    • Atopic dermatitis

     

    Presence of eosinophils at given site is hallmark of type 1

     

    Atopy: Overactive TH2 immunity = More IL-4 and IgE genetic predisposition to type 1 immediate hypersensitivity

    • Itching

    • Redness

    • hairloss

     

    Main players in type 1

    • Mast cells

    • IgE

    • Eosinophils

    • Basophils

    • TH2 cells and release of IL-4

     

    Sensitisation phase

    • B cells make IgE against that allergen (TH2 switching to IL-4)

    • IgE binds to surface of mast cells creating sensitized mast cell

     

    Re-exposure phase

    • Mast cells are re-exposed to allergen causing them to degranulate and release histamine, prostaglandins/leukotrienes, chemotactic factors for neutrophils and eosinophils

    • These can restrict smooth muscle in airways, vasodilation, acute inflammation, nerve endings causing itchiness

     

    Hours after

    • Eosinophils and macrophages

     

    Examples of Type 1

    • Allergy

    • Anaphylaxis

    • Asthma

    • Hay fever

    • Allergic conjunctivitis

    • Hives

     

     

     

     

    Type 2 Antibody mediated cytotoxic

    •  

    • Cytotoxic: cell death (destroyed by antibodies)

     

    • Inflammation

    • Cell destruction

    • Complement

     

    Main players in type 2

    • Antibodies = IgG and IgM good at binding to complement and initiating classical pathway

    • Macrophages phagocytose

    • NK cells kill

     

     

    Examples

    • Incompatible blood transfusion (RBC's have surface antigens)

    • haemolytic disease of newborn

    • Autoimmune haemolytic anaemia

    • Autoimmune thrombocytopaenia (kills platelets)

    • Graft rejection

     

     

    Incompatible blood transfusion

    • Lysis of RBC's in incompatible blood transfusion causes high concentration of free haemoglobin being released which can be damaging to kidney

    • Potassium also released

    • Blood clotting

    • Complement activation

    • Mast cells degranulate and vasoactive molecules produced

     

    Haemolytic disease of newborn

    • Female sensitized to foetal foreign blood group antigens during pregnancy

    • Makes Ab against foetal antigens

    • Newborn absorbs colostrum with antibodies

    • These antibodies taken up by newborn and react with antigens on red blood cells of newborn

    • Rapid haemolysis (mostly in horses and cats)

    • Increased pregnancies can be more severe

     

    Antibody reacts with surface of normal cells destroying them via complement, opsonisation, phagocytosis, cytotoxic cells (NK)

    • Lead to cell lysis and membrane attack complex

    • Lesions result from cell destruction

     

     

     

     

    Type 3 Immune complex hypersensitivity

     

    • Antigen-antibody complexes mediate tissue damage

    • Also mediated by antibodies but no cytotoxicity

     

    IgG and IgM

    • Immune compelxes

     

    Immune complexes form by antigen and antibody complexing together leading to complement activation

    • Occurs with subsequent exposure

    • May activate locally or circulate and be deposited in blood vessel walls = systemic

     

    Phagocytic cells often recruited

     

    C3a and C5a lead to inflammation

     

    Examples

    • Arthus reaction

    • Serum sickness

    • Lupus (deposition of immune complexes)

     

    Antigens, antibodies and complement come together to form an immune complex

    • Antibody binding causes classical pathway

    • Complement activation also releases C3a and C5a, neutrophil accumulation = inflammation and tissue damage

     

    Arthus reaction

    • Local tissue inflammatory reaction

    • Immune complexes deposited at site of penetration

    • Sometimes associated with vaccine = high local conc of antigen at site, high circulating antibodies

    • Pain, swelling, thrombosis occurs at site

    • Local vasculitis due to immune complexes in blood vessels = inflammation

    • Occurs if there are high local concentrations of antibodies

     

    Serum sickness

    • Damage to kidneys

    • Anaemia

    • Thrombotyopaenia

    • Vasculitis

    • Arthritis

     

    • Depends where immune complex deposits

     

    Phagocytic cells can remove immune compelxes

     

    Soluble immune complexes deposited in vessel walls

    • Presentations

    • Neutrophil accumulation: arthritis

    • Deposited in glomeruli: inflammation/nephritis

    • Arterial intima: neutrophil accumulation = arteritis

     

    Acute

    • Large dose of foreign antigen administered

    • Patient needs treatment with tetanus antiserum

     

    Chronic

    • Multiple small intravenous doses

    • Chronic damage to basement membranes

     

     

     

     

    Type 4 Delayed Type hypersensitivity

     

    • Different from other types because it is cell mediated by T cells

    • Delayed, prolonged onset

    • Can occurs days after exposure to antigen

    • Primarily cell mediated: antigen specific TH1 cells and its cytokines

    • Contact dermatitis

     

    Main players

    • Cytokines

    • T cells (TH1)

     

    Sensitisation phase is about generating TH1 cells and antigen specific memory TH1 cells

     

    Subsequent exposure

    • Reactivation of memory T cells

    • Drive inflammation

     

    Once TH1 cells are reactive usually in lymph node, go to site

    • Release cytokine IFN-Y

    • Recruit other inflammatory cell tissue damage at site of injection

     

    Detected by presence of memory T cells at least 72 hours after exposure

     

    Delayed type hypersensitivity

    • Injection

    • Tuberculin skin test for TB

    • Severity depends on number of Memory T cells present

     

    Uptake of antigen by APC's

     

     

    Phase 1

    • Migrate to draining lymph node

    • Present to naïve T cells

    • They respond and proliferate and secrete cytokines

     

    Phase 2

    • TH1 effector cells migrate to site

    • Release cytokines/chemokines

    • Recruit inflammatory cells

     

    Contact dermatitis

    • Syndromes for type 4 hypersensitivity

    • Antigen is often insect venom, micro bacterial proteins

    • Often caused by haptens penetrating skin and attaching to self proteins in epidermis and recognised as foreign

    • Exposure to foreign material

    • Skin thickening and fibrosis

     

     

     

    Contact hypersensitivity

    • Absorbed through skin

    • Hapten

    • Attach to self epidermal proteins and recognised by immune system (poison ivy)

     

     

     

    2 types of immunological disorders

     

    Primary

    • Genetic

    • Innate and adatpive

     

    Secondary

    • Acquired

     

     

     

     

     

    Innate deficiency

    • Complement deficiency cause extracellular bacterial infections

    • Phagocytic deficiency

     

     

    1. Defects in entry to inflamed tissues

    • Mutations cause white blood cells stop adhering to endothelium

    • Neutrophils can't exit blood vessels

    • Severe bacterial infections

    • Adhesion deficiencies

     

    • Symptom = high levels of neutrophils because they can't leave blood

    • Red setters and Holsteins  

     

    1. Cyclical or severe neutropenia

    • Grey colie syndrome, light coloured

    • Low levels of neutrophils

    • Effects bone marrow, so platelets and monocytes can also be affected

    • Cyclical function in number of blood cells, especially white

    • Take blood multiple times

    • Issue with stem cell growth factors

    • Bacterial infections

     

    1. Defects in neutrophil granules (also NK cells and CTL's)

    • Neutrophil number are still there but poor function due to defect in their granules

    • Susceptible to bacterial infections

    • Decreased colour because melanin granules can also be affected

     

     

     

    Adaptive

    • Cellular or antibodies

    • Number of cells may be normal but there could be a deficiency in the function

    • Often issues in progenitor cells

    • B and T cell deficiencies are worst

     

    Issue in lymphoid precursors = combined immunodeficiency (B and T cells)

     

    Thymic aplasia = T cells mostly effected

     

    Bone marrow/Bursa = B cells don't develop properly, can't make antibody = agammaglobulinemia

     

    • IgA deficiencies if problem further down

     

    Defects in APC's

    • Issues in antigen presentation to T cells

    • Causes Problems in other cells

     

    1. B cell deficiencies

    • Antibody deficiency

    • More likely to die from extracellular bacteria disease

    • Selective Ig deficiencies

    • Sharpies and German shepherd = deficiency in IgA

     

    1. T cell deficiencies

    • More likely to die from viral infections

    • Viruses replicate in cytoplasm and are killed by cytotoxic T cells

    • Mild defects in thymus developments

     

    1. Combined T and B deficiencies

    • Reoccurring infections

    • Lack of stem cell development

    • Variety of mutations can cause it

    • CD4 both

    • Defects in antigen receptor genes

    • Defects in cytokine genes

    • Defects in antigen presentation

     

    • Severe combined immunodeficiencies (SCID)

    • Pneumonia most common in equines

     

     

     

    Secondary

     

    • Previously had normal immune function

    • Acquired

    • Common

    • Cytotoxic drugs, chemotherapy, overexercise

    • Tumours

    • Old = thymic involution = thymus shrinks with age and less naïve T cells leave thymus

     

    Immunosenescent old age

    • thymic involution = thymus shrinks with age and less naïve T cells leave thymus

    • Decrease in circulating CD4 T cells

    • Fewer naïve cells leave bone marrow and thymus

     

    • Old animals still have high levels of serum antibodies and mucosal IgA

    • Older animals have good recall for secondary immune responses

    • Lesser ability to mount primary immune response

     

    Medically induced immunosuppression

     

     

    Virally induced immunosuppression

    • Virus kills B and T cells

    • Can destroy lymphoid organs

    • Retroviruses in cats

     

    Intense excessive exercise can cause stress and high levels of cortisol suppresses immune response

     

    Tumours

    • Release molecules that suppress immune function

    • Impairment of T cell proliferation

     

     

     

    Autoimmune disease

    • Autoreactive lymphocytes escape and enter lymphoid organs = no central tolerance

    • Immune system responds to self antigen via self reactive T and B lymphocytes

    • Central and peripheral tolerance disrupted

     

    Mechanisms of autoimmunity

    • Predisposed factors

    • Environmental factors

    • MHC genes

    • Characterised by tissue damage = result of hypersensitivity reactions

    • Autoreactive T cells or self reactive antibodies

    • Excessive response to allergens

     

    • Organ specific = diabetes, thyroiditis, uveitis

    • Systemic immunological = rheumatoid arthritis

     

    Pathogenesis of autoimmunity

    • Normal immune responses not around when self tolerance develops (recognised as foreign)

    • Molecular mimicry = microbe changes its antigens to be similar to host antigens, immune system targets own cells

    • Failure of normal regulatory mechanisms, reactive lymphocytes are not deleted in bone marrow  or thymus