Inappropriate immune responses

• what are the 4 hypersensitivity reactions?

  1. immediate (allergy)

  2. autoantibodies (AI)

  3. deposition of immune complexes (AI)

  4. T cell mediated tissue injury (AI)

  
• immediate hypersensitivity


  - stimulation of mast cells by crosslinking of FCR bound IgE

  - v.rapid after antigen exposure - response increases after each exposure

  - called allergy or atopy = strong genetic disposition
• what do mast cell mediators cause in immediate hypersensitivity?

  increased vascular permeability, vasodilation, bronchial/smooth muscle constriction and local inflammation = mast cells release histamine

  
• immediate hypersensitivity treatment?

  antihistamines
• allergens


  - usually require repeated exposure before substance triggers immune response

  - many small, glycosylated molecules with high solubility in body fluids
• why do allergens not trigger innate immune response?

  lack of epitopes = no Th1 or macrophage activation so straight to B cells and IgE
• what are the 3 mechanisms for autoantibodies?

  1. activate complement and stimulate phagocytosis (haemolytic anaemia)

  2. can recruit neutrophils which cause tissue damage (glomerular nephritis)

  3. can bind to receptor and stimulate or inhibit function (Grave's disease)
• autoantibody treatment?


  radioactive iodine, anticholesterases (myastheria gravis)
• cause of immune complexes?

  - can occur after multiple injections of ag (immunisation)

  - deposition usually occurs in small vascular beds, joints and renal glomeruli

  - leads to complement activation and FCR mediated responses

  - systemic disease

  
• immune complexes treatment?

  anti-inflammatory steroids
• cell mediated tissue injury

  - delayed type of hypersensitivity and cytotoxicity

  - mediated by Th1 and CD8 cells

  - release IFNy to activate macrophages and TNF to induce inflammation

  - tissue damage caused by hydrolytic enzymes, ROIs, cytokines

  - prototype disease = type I diabetes

  
• cell mediated tissue injury treatment?


  insulin
• what is autoimmunity?


  - disturbance in the immunologic tolerance of self-antigens

  - once initiated can result in epitope spreading resulting in chronic disease

  - systemic or organ specific

  
• AI factors


  genetic susceptibility and environmental triggers
• name 2 examples of AI diseases

  1. rheumatoid arthritis

  2. IBS
• what is rheumatoid arthritis?

  the inflammation and destruction of joints, autoantibodies may also be involved = systemic

  
• what is IBS?


  - mainly mediated by cytokines

  - can occur after chronic infection (e.g. TB)

  - mainly treated with anti-inflammatories (NSAIDS/SAIDS) and disease modifying agents (methotrexate)

  
• AI genetic susceptibility


  - most diseases are polygenic

  - often associated with HLA (e.g. HLA-DR4 linked to increased risk of RA)

  - females more likely to develop AI diseases

  
• transplantation immune response


  - recognise donor's MHC as foreign

  - donor tissue is killed by Tc, Th cells and antibodies

  - therefore requires blood and tissue typing (ABO, HLA systems) as a closer match decreases risk of rejection

  - opposite is Graft Vs Host Disease (GVHD) = donor tissue attack recipient cells/tissues

  - easiest option is a transplant from an identical twin
• blood typing

  - ABO system

  - everyone has basic glycolipid antigen (O), but some have attached carb groups (A or B)

  - these produce antibodies against the carbs we don't have = e.g. A has anti B antibodies with O having anti A and B antibodies

  - recipient of a transplant mustn't have antibodies against the donor antigen

  
• tumours


  - most weakly immunogenic = mainly seen as 'self'

  - grow rapidly and overwhelm immune system

  - few tumour specific antigens (oncoproteins) or self antigens that are usually hidden

  - mainly targeted by CTL and NK cells
• tumour treatment


  antibodies, vaccines, costimulation
• what is leukaemia?


  - cancers affecting immune cells

  - often due to chromosomal translocations that lead to constitutive activation of kinases and growth pathways

  
• what are lymphomas?


  - cancers of lymphatic tissue

  - B cell lymphoma is due to translocation and over-expression of bcl-2 (pro-survival)

  - aim to use immune-based therapies (antibodies, fusion constructs to decrease mutant cells)

  - conversely agents that boost T cell function have been shown to be efficacious

  
• what are the 2 types of immunodeficiency?

  1. congenital

  2. acquired
• congenital immunodeficiency


  - the inability, due to an individual's genotype, to produce specific antibodies or T cells

  - x-linked agammaglobulinemia

  
• acquired immunodeficiency


  - result of infection, cancer or drug treatment

  - HIV/AIDS
• HIV


  - infects dendritic cell and carried to lymph nodes

  - activate CTLs and antibody production = results in partial control of infection

  - infects T cells via CD4 and chemokine receptors

  - gradually causes lymphopenia

  - patient eventually dies of opportunistic infections