Hypersensitivity PDF

Autoimmune disorders: Animal Models What are immunodeficient mice? Immunodeficient mice refer to the mice with defects in one or more immune components (such as T, B, NK cells) in the immune system. Why are immunodeficient mice used in research? Triple immunodeficient mice are capable of hostin...

Autoimmune disorders: Animal Models What are immunodeficient mice? Immunodeficient mice refer to the mice with defects in one or more immune components (such as T, B, NK cells) in the immune system. Why are immunodeficient mice used in research? Triple immunodeficient mice are capable of hosting xenograft cells, tissue, and human immune system components, thus enabling studies of tumor biology and immune-oncology, infectious disease, graft-versus-host disease (GvHD), hematopoiesis, and tissue transplant studies. Nude Mice Nude mice were the first immunocompromised mouse strain to be used in cancer research. Our nude mouse models are ideal for cancer studies because they don't reject tumor cells. These strains give insight into multiple forms of immune deficiencies. Caused by a genetic mutation, nude mouse models lack a normal immune system and thymus gland. They have a repressed immune system due to reduced number of T cells. Nude mice are ideal for tumor and tissue studies because they have no rejection responses and are hairless, making it easier to identify tumors.  Scid mouse Model SCID stands for severe combined immunodeficiency disease. This means that SCID mice show a severe immunodeficiency that genetically affects both B and T lymphocytes. What are the uses of SCID mice? SCID mice have allowed for increased research on a wide range of topics, including the development and pluripotency of human HSC, human-specific diseases and their interactions with the human immune system, vaccination, and cancer The mutation causing SCIDs in mice was discovered by Melvin and Gayle Bosma in 1983 in the CB/17 mouse line. SCIDs occurs in these mice due to a mutation in the gene for protein kinase, DNA activated, catalytic polypeptide (PRKDC), which plays a role in repairing double-stranded DNA breaks. This has implications for B and T cell receptor development, which is dependent upon such double-stranded breaks and subsequent repairs in order to rearrange V, D, J or V and J segments. Mice with SCIDs have lymphocyte progenitors, but these cells are unable to survive to maturity. This results in a lack of B and T cells in the thymus and in the secondary lymphoid organs, such as the spleen and lymph nodes. Some SCID mice are able to produce monocytes, granulocytes, and red blood cells from the hematopoietic stem cells (HSC) present in their bone marrow. Due to their immunodeficiency, mice with SCIDs often die young if not kept under extremely sterile conditions. SCID mice can serve many functions in research, particularly in the study of human physiology and disease.The study of human physiology in human models is often made impossible due to ethical limitations, high financial expense, and low availability of model environments. Furthermore, results gleaned from the study of human cells ex vivo may not be indicative of their functions in vivo. Due to their immunodeficient state, SCID mice are able to accept human hematopoietic stem cells harvested from human bone marrow or thymus. This can lead to the development of human adaptive immune cells, such as B and T lymphocytes, within SCID mice, and for subsequent study of human cells in vivo.  Hypersensitivity Hypersensitivity reactions are exaggerated or inappropriate immunologic responses occurring in response to an antigen or allergen. Type I, II and III hypersensitivity reactions are known as immediate hypersensitivity reactions because they occur within 24 hours of exposure to the antigen or allergen. The four types of hypersensitivity are: Type I: reaction mediated by IgE antibodies. Type II: cytotoxic reaction mediated by IgG or IgM antibodies. Type III: reaction mediated by immune complexes. Type IV: delayed reaction mediated by cellular response. Type I hypersensitivity Type I hypersensitivity is an immediate reaction (within minutes) mediated by IgE antibody, which results in allergy, anaphylaxis and atopic disease. When an individual first encounters an antigen, their immune system may produce large amounts of IgE antibodies against this specific substance. These IgE molecules attach themselves to mast cells and basophils. The individual is now ‘sensitised’ to the antigen. When this antigen is encountered again, it will cause cross- linking of the bound IgE and degranulation of mast cells and basophils, releasing potent vasoactive molecules such as histamine. This leads to the signs and symptoms of allergy, and if severe can cause anaphylaxis. Type II hypersensitivity Type II hypersensitivity is an IgG or IgM antibody- mediated cytotoxic reaction occurring in hours to days, which results in pathologies such as haemolytic disease of the newborn, autoimmune haemolytic anaemia and Goodpasture’s syndrome. An individual may possess or develop IgG and IgM antibodies directed against cell surface or extracellular matrix antigen. These antibodies can cause damage to cells or tissues (cytotoxicity) either directly by cell surface receptor binding, via activation of the complement pathway or by antibody-dependent cellular cytotoxicity. Pathology is dependent on the target of the antibody. If antibodies are directed to cell surface antigen on red blood cells this can cause haemolytic anaemia, if they are targeted to type IV collagen in the basement membrane this can cause Goodpasture’s syndrome.   Goodpasture syndrome is a group of acute illnesses that affects the lungs and kidneys. It involves an autoimmune disorder. Normally, the immune system makes antibodies to fight off germs. But with Goodpasture syndrome, the immune system mistakenly makes antibodies  Systemic that attack the lupus erythematosus lungs (SLE), andmost is the kidneys. common type of lupus. SLE is an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels.  How does streptococcal infection cause glomerulonephritis? Glomerulonephritis may develop a week or two after recovery from a strep throat infection or, rarely, a skin infection caused by a streptococcal bacteria (impetigo). Inflammation occurs when antibodies to the bacteria build up in the glomeruli.  The Mantoux tuberculin skin test (TST) is one method of determining whether a person is infected with Mycobacterium tuberculosis. Type III hypersensitivity Type III hypersensitivity is an antigen-antibody immune complex- mediated reaction, which can occur over hours, days or weeks. Examples include serum sickness, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and post-streptococcal glomerulonephritis. Soluble antigen in the circulation is bound to by antibodies (most commonly IgG and IgM) forming immune complexes. These complexes can precipitate out of the circulation and deposit in certain tissues, notably blood vessels, synovial joints and the glomerular basement membrane. These complexes trigger the classical complement pathway, leading to the recruitment of inflammatory cells including neutrophils that release enzymes and free radicals causing tissue damage. These inflammatory processes cause pathology in diseases such as rheumatoid arthritis, where immune complexes damage the filtration systems vital in synovial fluid formation. Type IV hypersensitivity Type IV hypersensitivity is also known as delayed hypersensitivity, as the reaction typically occurs 24 to 72 hours after antigen exposure. Unlike types I to III, it is not antibody-mediated but T cell- mediated. It is involved in the processes of contact dermatitis and the tuberculin skin test (Mantoux). When an individual first encounters an antigen, it can be processed by antigen-presenting cells and lead to sensitisation of T helper cells. On subsequent exposure to this antigen, these T helper cells will become activated and lead to an inflammatory response involving several immune cells such as macrophages, though there will be a delay of 24 to 72 hours as cells are recruited to the site of antigen exposure. This can cause local tissue inflammation and damage as seen in contact dermatitis when substances such as nickel or poison ivy contact the skin, or in the Mantoux test where proteins from M. tuberculosis are injected intradermally and an indurated area forms in able 1. The key features of the four types of hypersensitivity reaction. Type Mediated by Timeframe Examples 1) Type I hypersensitivity IgE antibody Immediate (minutes) Allergy, anaphylaxis, atopy 2) Type II hypersensitivity IgG or IgM antibody (cytotoxic) Hours to days Haemolytic disease of the newborn, autoimmune haemolytic anaemia, 3) TypeGoodpasture’s III hypersensitivity syndromeAntigen-antibody immune complexes Hours to days/weeks Serum sickness, RA, SLE, post- streptococcal glomerulonephritis 4) Type IV hypersensitivity T cells Delayed (24 to 72 hours) Contact dermatitis, tuberculin skin test  Specific impaired functions in Lymphoid and Myeloid lineage What is the lymphoid lineage and myeloid lineage? Lymphoid lineage cells include T, B, and natural killer (NK) cells, while megakaryocytes and erythrocytes (MegE) as well as granulocytes and macrophages (GM) belong to the myeloid lineage.