Immunology Flashcards
A hypersensitivity reaction is…
An excessive immune response to antigens* that do not normally cause tissue damage
Autoreactive T cells or autoantibodies cause tissue damage through hypersensitivity reactions types II, III, IV
*antigens could be infectious agents, environmental substances or self-antigens
Autoimmunity reactions are…
failure of self-tolerance resulting in immune reactions against self-antigens
Process in which immature lymphocytes are taught to differentiate btw host and non-host. Cells that show a high affinity to self-antigens are eliminated
Central tolerance
In the thymus for T cells
In the bone marrow for B cells
Process occurring in secondary lymphoid organs, where mature lymphocytes showing a high affinity for self-antigens are eliminated
Peripheral tolerance
eliminated by Tregs
Causative factors contributing to a breakdown of tolerance causing autoimmunity
Genetic predisposition
- familial
- different MHC alleles
- common polymorphisms
- rare genetic diseases
Environmental factors
- infections
- drugs
- UV radiation
Examples of organ specific autoimmune diseases
Brain: MS
Thyroid: hashimoto’s
Stomach: pernicious anaemis
Adrenals: addison’s disease
Pancreas: type I DM
examples of non-organ specific (systemic) autoimmune diseases
Dermatomyositis SLE Scleroderma Rheumatoid arthritis Coeliac
General management of autoimmune conditions
Anti-inflammatory drugs (e.g. corticosteroids)
Immunosuppressive drugs
Replacement of function of damaged organ (e.g. hypothyroidism, type I DM)
Neutrophils target infections caused by…
Bacteria
Fungus
Monocytes target infections caused by…
Fungus
Eosinophils target infections caused by…
Parasites
T- lymphocytes target infections caused by…
Funcus
Viruses
PJP
B-lymphocytes target infections caused by…
Bacteria
Type I hypersensitivity is also known as…
Allergy
Type II hypersensitivity is also known as…
Antibody mediated hypersensitivity
Type III hypersensitivity is also known as…
Immune complex mediated hypersensitivity
Type IV hypersensitivity is also known as…
delayed hypersensitivity
(usually a 48-72hr delay btw antigen exposure and clinical effect)
a genetic tendency to produce IgE to normally innocuous environmental allergens
Atopy (40% of the population in Western society are atopic)
Have the genetic potential to produce allergic reactions but most won’t as allergy arises through a combination of genetic and environmental factors
Pathogenesis of allergy (type I hypersensitivity)
Allergen exposure --> B-cell --> IgE --> Early Phase Response (mins): degranulation of mast cells (release of preformed mediators: histamine, heparin...) \+ Late Phase Response (hours): - Synthesis of new mediators (prostaglandins, leukotrienes) - Th2 cytokines eosinophil mediators --> Allergic reaction - mucosal oedema - capillary leakage - secretions - smooth muscle contraction - vasodilation
Diagnosis of allergy
Skin prick tests
IgE levels (RAST)
Histamine levels
Treatment of allergy
Patient education
Allergen avoidance
Antihistamines
Corticosteroids
Leukotriene antagonists
Desensitisation immunotherapy
Type II hypersensitivity is mediated by which antibodies
IgG or IgM
((antibodies bind to antigens and cause damage through complement activation, stimulation of phagocytes, ADCC or directly affecting the target cell))
Examples of clinical disorders caused by type II hypersensitivity reactions
Haemolytic reactions (autoimmune/ following transfusions)
Haemolytic disease of the newborn
Hyperacute graft rejection
Some organ specific autoimmune diseases (graves, myaesthenia gravis)
Treatment + prevention of type II hypersensitivity reactions
Prevention:
- cross matching of blood
- tissue typing
- detection of rhesus incompatibility in pregnancy
Immune suppression
Type III hypersensitivity clinical conditions arise due to…
abnormal/excessive formation of antigen-antibody (immune) complexes and deposition in tissues
Caused by defects in the antigen or antibody
Presentation of a type III hypersensitivity reaction
- Serum sickness
- caused by immune complexes formed in the circulation and deposited throughout many tissues
- a systemic illness - Arthus reaction
- immune complexes are formed in tissues
- a localised disorder
Clinical disorders caused by type III hypersensitivity reactions
Extrinsic allergic alveolitis (farmer’s/bird fancier’s lung)
Post-streptococcal glomerulonephritis
Chronic infections (e.g. leprosy, malaria)
Tumours
SLE
Diagnosis of type III hypersensitivity caused conditions
Clinical features
Tissue biopsy
Circulating immune complex tests
Precipitating antibody tests
Treatment of type III hypersensitivity caused conditions
Antigen elimination (e.g. infection/tumour)
Removal of immune complexes
Immunosuppressive therapy
Type IV hypersensitivity reactions are mediated by…
and directed against…
TH1 and/or TH17 cells
and the cytokines they secrete
Directed against
- inert environmental substances*
- infectious agents that have evolved to evade the immune response (e.g. mycobacteria)
*often in the form of a HAPTEN (as too low in molecular weight to produce a response themselves) bound to a host protein CARRIER
((only hypersensitivity reaction to not involve antibodies))
Pathogenesis of type IV hypersensitivity reaction
hapten+carrier or microorganism
–>
presented on HLAII on an antigen presenting cell
–>
TH1/TH17 cytokine overproduction/dysregulation
–>
inflammation
Treatment of type IV hypersensitivity caused conditions
prevention / avoidance of contact with antigens*
anti-inflammatory drugs (e.g. corticosteroids)
Immunosuppressants (eg block TNF, IL-6, B cells – often monoclonal antibodies)
*contact dermatitis is caused by type Iv hypersensitivity
Clinical disorders caused by type I hypersensitivity reactions
Allergic rhinoconjunctivitis asthma urticaria, angioedema, eczema food allergy anaphylaxis (due to foods, insect venoms, drugs, latex)
Major histocompatibility protein I (MHCI) is expressed on…
and its function is…
Expressed on all nucleated cells and platelets
Present self-antigens / antigens produced by intracellular pathogens…
…to CD8+ cytotoxic T lymphocytes
Major histocompatibility protein II (MHCII) is expressed on…
and its function is…
Expressed on professional antigen presenting cells (APCs)
(e.g. dendritic cells, macrophages, B lymphocytes)
Present exogenous/extracellular antigens from pathogenic invaders…
…to CD4+ helper T lymphocytes
Difference btw B and T lymphocytes in antigen detecting
B-cells express a B cell receptor (functionally an antibody) which detects antigens directly
T-cells only recognise antigens that are processed by an APC* and presented by an MHC molecule
*professional or non-professional
T helper cells (Th) (CD4+)
Function
Activated by antigen presentation by MHCII
Secrete cytokines which have different functions
TH1 - IFNγ, IL-2, TNF (host defence against intracellular pathogens, role in autoimmunity + chronic inflammation)
TH2 - IL-4, IL-5, IL-13 (host defence against helminths, role in allergy)
TH17 - IL-17, IL-22 (host defence against extracellular bacteria and fungi, role in autoimmunity and inflammation)
((*IFN = interferon TNF = tumour necrosis factor IL = interleukin))
T cells that exert a controlling and regulatory influence on immune responses
T regulatory cells (TReg)
Cytotoxic T cells (Tc) (CD8+)
function
Activated by antigen presentation by MHCI
Secrete IFNγ
Kill cells infected by intracellular microbes and tumour cells
Primary lymphoid organs
+ functions
Thymus - where T cells mature and those responding to self-antigens are deleted
Bone marrow - where B cells mature and those responding to self-antigens are deleted
Secondary lymph organs
+ functions
Lymph nodes
Spleen
Tonsils + adenoids
Gut associated lymphoid tissue (GALT) (e.g. Peyer’s patches)
where lymphocyte responses to foreign antigen are initiated
Structure of antibodies
2 longer heavy chains
2 shorter light chains
Each chain has a variable region (at the “top”) and a constant region
2 antigen binding sites (Fab) (at the “tips” of the Y)
an Fc region (the “stalk” of the Y)
Functions of antibodies
Antigen binding Immune complex formation Opsonisation Complement activation Cellular cytotoxicity (ADCC)
Components of the innate immune system
Physical + chemical barriers
Cells - phagocytes(macrophages, neutophils), eosinophils, basophils, mast cells, Natural Killer cells (NK)
Complement system
Pattern recognition receptors
transfer of tissue between different sites within the same organism
An autograft transplant
e.g. skin graft
transfer of tissue between genetically identical individuals
ie. identical twins
An isograft transplant
also known as syngeneic
transfer of tissue between genetically non-identical members of the same species
An allograft transplant
(donor and recipient must be carefully tissue matched)
transfer of tissue between species
A xenograft transplant
(highest risk of rejection)
examples of transplants which are carried out with varying degrees of frequency and success
kidney, heart, lung, skin, bone, pancreas / islets of Langerhans, small bowel, bone marrow, cornea, uterus
damage done by the immune system to a transplanted organ
Rejection
Criteria that must be met before transplantation
- Good evidence that the damage is irreversible
- Alternative treatments are not applicable
- The disease must not recur
Criteria that must be met to minimise the risk of rejection with a solid organ transplant
- ABO matching
- Close tissue matching (esp. HLA)
- Prophylactic immunosuppressive therapy
((HLA antigens are expressed in differing densities on different organs…
so different organs require differing degrees of ‘closeness’ in tissue matching and differing degrees of immunosuppressive therapy after transplantation))
Examples of major* antigens which donor and recipient must share in order for a graft to survive
- ABO blood group antigens
- Major histocompatibility antigens (HLA)*
((minor histocompatibility antigens are less well defined and mismatch is only occasionally a clinical problem))
*((HLA antigens are expressed in differing densities on different organs…
so different organs require differing degrees of ‘closeness’ in tissue matching and differing degrees of immunosuppressive therapy after transplantation))
Tissues into which foreign grafts can be placed with no tissue or blood group matching is required because there is little blood or lymphatic supply to the tissue are called…
PRIVILEGED SITES
e.g. the cornea
Graft rejection occurs due to…
histocompatibility (HLA) differences between donor and recipient
((ABO mismatches are very rare and are usually due to human error in matching))
A rejection reaction that occurs within minutes of grafting is called…
and is caused by…
Hyperacute
caused by pre-formed antibody against HLA/ABO antigens
A rejection reaction that occurs within 2-5 daysof grafting is called…
and is caused by…
Accelerated
caused by T cells
A rejection reaction that occurs within 7-21 days of grafting is called…
and is caused by…
Acute
caused by T cells
A rejection reaction that occurs within months-years of grafting is called…
and is caused by…
Chronic
multifactorial in cause
A post transplant condition in which donor immune cells cause tissue damage in recipient skin, gut, liver and immune cells
Graft versus host disease (GVHD)
principally occurs in bone marrow transplantation
Graft versus host disease occurs in a specific set of circumstances…
+ prevention
- functioning T cells in graft
- defective T cells in recipient
- HLA mismatch
prevention:
- careful close tissue matching
- deplete graft of T cells in vitrio prior to grafting
The problem with xenografting from pigs
+ solutions
All humans have an IgM cantibody directed against pig antigens
Solutions:
- remove IgM antibody from recipients
- genetically modified (silenced) pigs
- “humanised” transgenic pigs (chimeras)
Potential complications of transplantation
Graft rejection Graft versus host disease (GVHD) Infection (due to graft or immunosuppressive therapy) Recurrence of original disease Ethical, surgical problems etc.
Immunosuppressive/ immunomodulatory drugs
examples
Corticosteroids Azathioprine Cyclophosphamide Cyclosporin & Tacrolimus Sirolimus Mycophenolic acid
Monoclonal antibody production
Fusion of:
- plasma cells producing the desired specific antibody
- neoplastic myeloma cells
Results in an immortalised single clone cell line that indefinitely produces the pure desired antibody
Can be used:
- unconjugated = as they are harvested
- conjugated = linked to drugs which are delivered to target cells
Aims of cytokine therapy
+ examples
To inhibit the activity of harmful cytokines
- anti-IL-1
- anti-TNF
- anti-IL-2
or
To enhance the activity of beneficial cytokines
- IFNα
- IFNγ
Immunoglobulin therapy consists of…
purified immunoglobulin preparations containing IgG extracted from pooled donor blood
Given to patient by IV infusion (can be I/M or S/C)
Indications for immunoglobulin therapy
- replacement therapy in antibody deficiency
- immune modulating therapy in certain inflammatory/autoimmune conditions, e.g…
- allergic disorders
- ITP
- GVHD
- vasculitis
- myaesthenia
- SLE
- autoimmune neuropathies
Problems associated with immunoglobulin therapy
Adverse reactions during infusions
Transmission of infection (particularly hepC)
Process in which patient’s plasma is filtered off and replaced by normal donor plasma
Plasma exchange
(used in some autoimmune disorders which involve formation of autoantibodies or immune complexes)
Process in which patient’s plasma is filtered off and replaced by albumin solutions
Plasmapheresis
(used in some autoimmune disorders which involve formation of autoantibodies or immune complexes)
Non pharmacological immunotherapies
Monoclonal antibodies
Cytokine (receptor) therapy
Plasma exchange/ plasmapheresis
Antibody isotypes
The 5 shapes of antibody found in humans
IgA IgD IgE IgG IgM
IgA is present in…
Secretions such as tears and breast milk
Important in mucous membrane immunity
IgE is involved in..
The immune response to parasites
The pathogenesis of allergy
The primary antibody response to an antigen is characterised by…
- a lag phase while B cells are differentiating into plasma cells and no antibodies are produced
- a low volume of IgM produced
((memory B cells are then formed))
The secondary antibody immune response to an antigen (at reinfection) is characterised by…
Memory B cells quickly proliferate + create plasma cells which produce…
fast release of a high volume of IgG
((IgG is also the only antibody isotype to cross the placenta))
Causes of secondary immune deficiency
More common than primary
Malnutrition infection immunosuppressive therapy malignant disease diabetes chronic renal failure splenectomy burns / surgery
Heterogeneous group of conditions that produce severe dysfunction / defective development in both T and B cells
management
Severe combined immune deficiency (SCID)
Management: early bone marrow transplantation (only cure)
Infections common in conditions with antibody defects
Bacteria: staphylococci, streptococci, haemophilus
Protozoa: guiardia
Viruses: echo, polio
Infections common in conditions with T cell defects
Viruses (CMV, herpes, measles)
Bacteria (mycobacteria, listeria)
Fungi (candida, arpergillus)
Protozoa (pneumocystis, cryptosporidiosis, toxoplasma)
