ic4 Flashcards
antibodies
bind to extracellular antigens, defence against foreign pathogen
types and functions of antibodies
1) IgG: neutralisation of microbes & toxins, opsonisation of antigens for phagocytosis by macrophages & neutrophils, activation of classical pathway of complement, antibody-dependent cellular cytotoxicity mediated by NK cells, neonatal immunity (maternal -> baby), feedback inhibition of B cells activation
2) IgM: activation of classical pathway of complement
3) IgA: mucosal immunity
4) IgE: eosinophil & mast cell mediated defense against helminths (worms)
mechanisms of antibodies
1) neutralisation: antibody blocks binding of microbes & cell infection
2) opsonisation: activation of phagocytes (classical pathway of complement activation)
3) clearance of immune complexes composed of bacteria and Ig by spleen
mechanisms of antibodies
1) neutralisation: antibody blocks binding of microbes & cell infection
2) opsonisation: activation of phagocytes (classical pathway of complement activation)
3) clearance of immune complexes composed of bacteria and Ig by spleen
T cells
effector CD4+ T cells: provide help for other immune cell subsets
effector CD8+ T cells: defend against extracellular pathogens, kill target cells
hypersensitivity reactions
same immune mechanisms that defend against microbial infections cause tissue damage when excessive/aberrant
4 types
hypersensitivity reactions - type 1: immediate hypersensitivity
. pathologic immune mechanisms: TH2 cells, IgE antibody, mast cells, eosinophils
. mechanisms of tissue injury and disease: mast cell-derived mediators (vasoactive amines, lipid mediators, cytokines), cytokine-mediated inflammation (eosinophils, neutrophils)
. process
1) first exposure to allergen -> antigen activation of T follicular helper cells & stimulation of IgE class switching (B cells)
2) production of IgE
3) binding of IgE to Fc epsilon receptor (high affinity for Fc region of IgE)
4) activation of mast cells: release of mediators
5a) release of pre-formed mediators by degranulation (vasoactive amines, lipid molecules) -> immediate hypersensitivity
reaction (minutes after repeat exposure to allergen) (responsiveness to anti-histamines)
or 5b) de novo transcription of cytokine genes -> late-phase reaction (6-24 hours after repeat exposure to allergen) (may
require corticosteroids to control)
. mast cells degranulation (release of mediators) increase vascular permeability & local edema
. e.g. Urticaria (hives), oedema
hypersensitivity reactions - type 1 e.g. Anaphylaxis
. severe, potentially life-threatening allergic reactions
. manifestations: shortness of breath, difficulty breathing, hypotension, tachycardia
. common precipitants: insect sting, drugs (penicillin)
. why drugs cause?
. penicillin form hapten-carrier conjugate with self protein, act as immunogen to generate anti-penicillin antibodies
. allergic reactions to penicillin develop when antibodies of IgE subclass form
. cross allergy: B-lactam antibiotics contain common B-lactam ring structure, cross-reacting anti-penicillin antibodies bind to
B-lactam ring structure, individuals with allergic reaction to one B-lactam ring react similar to others of same class
hypersensitivity reactions - type 2: antibody mediated diseases
. pathologic immune mechanisms: IgM, IgG antibodies against cell surface/extracellular matrix antigens
. mechanisms of tissue injury and disease: complement and Fc receptor mediated recruitment and activation of leukocytes,
opsonisation & phagocytosis of cells, abnormalities of cell function
. inflammation (activation of complement) & tissue injury (recruitment of leukocytes) triggered by antibody binding to antigen
on cell surfaces
. e.g. blood transfusion: antibody bind to antigen -> haemolysis
. e.g. penicillin induced haemolysis
. penicillin bind to protein on RBC surface, act as hapten, induce antibody production
. patient’s antipenicillin antibodies don’t react with penicillin, only when patient take penicillin again then antibody react with
penicillin-red cell complex: antibody bind to Fc receptor on splenic macrophage, RBC destroyed
hypersensitivity reaction - type 3: immune complex-mediated diseases
. pathogenic immune mechanisms: immune complexes of circulating antigens and IgM/IgG antibodies deposited in vascular
basement membrane
. mechanism of tissue injury & disease: complement of Fc receptor mediated recruitment & activation of leukocytes
. inflammation & tissue injury arising from deposition of antibody-antigen immune complexes in tissue
. antibody bind to soluble antigen -> cross-linking -> form immune complexes
. large immune complexes precipitate out of solution -> deposit in tissue
. site of organ damage: certain sites prone to immune complex deposition
hypersensitivity reactions - type 4 : T-cell mediated diseases
. pathogenic immune mechanisms: CD4+ ctokine-mediated inflammation, CD8+, CTLs, CT-cell mediated cytolysis
. mechanism of tissue injury and disease: macrophage activation, direct target cell lysis (both cytokine-mediated inflammation)
. cell-mediated immunity
. key role of sensitised T cells (no antibodies involved)
hypersensitivity reactions - type 4: antimicrobial effector functions of T cells
. phagocyte with ingested microbes in vesicles secrete cytokines -> macrophage activation (kill ingested microbes)/inflammation (killing of microbes)
. infected cell with microbial antigens in cytoplasm -> killing of infected cells
. effector CD4+ T cells provide help for other immune cell subsets
. cytotoxic T lymphocytes kill virus infected cell
autoimmune disease - self tolerance
. T/B cells normally do not mount immune response against self-antigens
. central tolerance: autoreactive immature lymphocytes deleted during development
. peripheral tolerance: additional mechanisms that act on mature lymphocytes to ensure self tolerance
autoimmunity
development of adaptive immune responses specific for self antigens due to breakdown of self tolerance
autoimmune disease
inflammation, tissue damage, physiological dysfunction due to autoimmunity
auto-antibodies that block ligand-receptor interactions
pathological anti-acetylcholine receptor antibodies in myasthenia gravis interfere with transmission across neuro-muscular synapse, abnormal muscle fatigue
auto-antibiotics that bind to & activate receptors
pathological anti-TSH receptor antibiotics found in Grave’s disease
. excessive thyroid hormone production no longer regulated by -ve feedback
. treatment: methimazole, propylthiouracil, surgery, radioactive ablation
immunodeficiency types
primary immunodeficiency, secondary immunodeficiency
primary immunodeficiency
intrinsic defect in immune system
rare
usually manifests in children
secondary immunodeficiency
underlying disease adversely affects immune system
much more common
may affect elderly
addressing cause may improve immune function
manifestations of immunodeficiency
1) infections: reactivation of latent infections, unusually frequent/recurrent/persistent infections, opportunistic infections: microbes present normally low virulence in healthy individuals with intact immune system but may affect immunocompromised individuals
2) increased incidence of cancer
3) immunosuppressant drugs (not antigen specific)
when is there a decrease risk in graft rejection?
Human Leukocyte Antigen (HLA) matching between donor & recipient decrease risk of graft rejection for both solid organ transplant (SOT) and haematopoetic stem cell transplant (HSCT)
graft rejection
. adaptive immune response to human antigen in transplanted cells perceived as foreign by recipient
. antibody & T cell responses contribute
types of transplants
1) syngeneic transplant: patient receive healthy stem cells to replace own (twins)
2) allogeneic transplant: most common, transfer stem cells from healthy donor to patient
histocompatibility genetics in humans
. HLA: alloantigens (antigens of allografts) serve as principal determinants of immune rejection
. human MHC molecules present peptide antigens to T cells
. HLA genes highly polymorphic (2 unrelated individuals likely express HLA that appear foreign to each other’s immune system
allogeneic T cell responses
. occur when recipient T cells recognise donor HLA as foreign
. due to immunological cross-reactivity for donor HLA molecules
. more closely related donor & recipient = less alloreactivity
allogenic antibody response
. pre-formed (from previous transfusion) / formed after transplant
. generate anti-HLA antibodies even before transplant
. ABO incompatibility (anti - A, anti - B antibodies
types of rejection in renal transplant
hyperacute rejection, acute rejection, chronic rejection
hyperacute rejection
within minutes of transplant
mediated by pre-formed anti-donor antibodies in recipient (specific for & bind to donor antigens expressed on graft endothelial cells)
effects: damage endothelium, vascular thrombosis, ischaemic necrosis of graft
pathogenesis: antibody binding -> activation of complement, recruitment & stimulation of phagocytes -> inflammation & tissue injury
acute rejection
days/weeks after transplantation
main cause of early graft failure
main causative factor: recipient CD8+ T cells, kill transplanted allogenic graft cells recognised as foriegn
pathophysiology: recipient T cells recognise allogenic HLA peptide complexes displayed by graft APC
chronic rejection
months/years after transplant
possible mechanisms:
1) alloreactive recipient CD4+ T cells activated by indirect allorecognition enter graft with recipient APC
2) recipient APC process & display graft alloantien -> alloreactive CD4+ T cells release cytokines
3) cytokines cause inflammation, stimulate fibroblasts, graft fibrosis, narrow graft blood vessels
haemapoetic stem cells transplantation indications
1) replace dysfunctional lineages in haematological situations
2) malignancy: blast (eradicate residual tumour cells) and replace HSC
complications of HSCT
1) infection
2) graft rejection/failure
3) graft vs host disease
problems of HSCT at the start
own bone marrow removed -> lower WBC count while awaiting donor -> HSC reconstitute immune system -> increase risk of infection
signs of successful graft
increase in absolute neutrophil count (ANC) after about 2 weeks
patterns of allogeneic responses in HSCT
host vs graft
antibody mediated response
graft vs host disease
host vs graft (HSCT)
T cell mediated response
. HSCT to recipient with residual functional immunity
. if recipient derived alloreactive CD8+ T cells reject donor HSC -> graft rejection/failure, marrow failure
antibody mediated response
. triger complement dependent cellular cytotoxicity (ADCC) against donor cells
graft vs host
administration of immunocompromised cells
histo-incompatibility between donor & recipient
inability of recipient to destroy/inactivate transfused cells
pathophysiology of acute graft vs host disease
HSCT infusion contain CD34+ HSC (reconstitute immune system in recipient) + mature T cells from donor
recognition of allogeneic MHC-peptide on recipient APCS by donor-derived mature T cells cause acute GvHD
