04 - January 30, 2013.docx

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Laboratory Medicine and Pathobiology
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LMP403H – January 30, 2013 EXAM: Shek usually asks multiple choice questions; Ni usually asks short answer questions; M asks short questions; multiple choice and some short answer Tolerance = not perfect; maintain “healthy” level Everyone has autoimmune activity – ex, in Western blot – lots of interaction of own leukocytes and own antibodies Understand – SOLID UNDERSTANDING – KNOW VERY WELL Be familiar – basic understanding Immunity is defense system – strong immune response needed Malignant tumours usually occurs past forty years old – young people less likely to develop tumours typically due to stronger immune surveillance and elimination – cell-mediated immune response decreases once reach particular age, allowing tumour development Immune tolerance – if not tolerant of certain antigens, have autoimmune disease – have adaptive immune system In short, need immunity and tolerance to be well balanced – this balance in multiple layers – the layers are not perfect, but in general, it’s fine Innate immunity – “same” is not identicial but in general the same Broad diversity – T cell and B cell have large repertoire B cell plasma mediated antibody generation – humoral response Metchnikoff – experiment: thorn embedded in starfish; overnight; saw the cells congregating around the thorn Both humoral and cellular immunity systems need to be tolerant to avoid autoimmune disease Innate vs acquired immunity Platelets – small cells in blood; while circulating, platelets near the vessel walls, while red blood cells, larger, tend to be in the middle of vessels – so platelets close to site of inflammation – Platelets contribute to leukocyte migration – move to site of infection Platelets can direct and destroy bacteria – co-culture bacteria dn platelet, bacteria tries to survive, platelets tries to destroy the bacteria – important for certain bacterial infections HIV patients – decreased platelet numbers Parasites – attack certain parasites, like malaria – transmitted by mosquitoes – live in red blood cells – once proliferate to certain level, red blood cells burst open Disease progress – Science 2009 paper – once malaria infected red blood cells, platelets stick to it, releasing chemicals to induce aptoptosis of malaria-infected cell – Platelets help lymphocyte homing CD40 ligand – molecule important for Ig class switching – if animal is deficient in this, difficult to switch classes – but this knockout mice, transfuse with normal platelets(contain large amount of CD40 ligand), can help B cell class switch Platelets contain large amount of TGF beta – positively support inflammation – important to immune suppressive cytokines – do platelets have immune regulatory function? Malignant tumour – Cancer Research paper – TGF beta could decrease function of NK cells Tumour infiltrated lymphocytes – if see many of tehse in tumour area, prognosis is good for patient Usually in early stage of malignant tumour, have these cells proliferating in tumours – anergy – lose certain function, cannot kill the tumour cells; able to kill in vitro but in vivo, unable to function/kill tumour cells Removing tumour may leave behind residual cells – tumour comes back Able to educate immune system – remove tumour so platelet interaction with malignant tumour could be new area for development of anti-tumour therapies Semple paper in Nav Rev Imm – platelets P-selectin needed in inflammation – mediate tethering of leukocyte – or for T cell/B cell to come to the site for proliferation Animal knockouts for P selectin – leukocyte cannot interact with vessel wall – but later, p-selectin is important to develop TH1 immune response, which is important for cell mediated immunity for anti- virus, anti-TB, anti-tumour Ni lab – found fibrinogen (major protein in blood circulation) is ligand of Beta 3 integrin – platelet has no nucleus but able to de novo synthesize p-selectin – platelets have remaining mRNA that can be translated into protein – p-selectin important for interacting with lymphocytes, for stem cells, etc. Platelets affect immune control/modulate/regulate immune response, including tolerance Platelets in immunology Innate immunity Direct interaction with T, B cells, etc. other cells Express p-selectin and regulate themselves – immunocompetent cells and affect adaptive immunity Contain large amounts of TGF beta – effect T regulatory cell develop, decrease immune response Blood paper – 2010 – Cara C. Bertozzi et al. Platelets regulate lymphatic vascular develppment through CLEC-2-2 SLP-76 signalling Remove CLEC 2 from platelet surface, these animals cannot separate blood cell vessels vs lymphatic vessels – if not separated, then not good for immune system Conglei Li – Advances in Hamtology 2012 Crosstalk between platelets and the immune system Close to site of inflammation Interaction between innate-adaptive imunity TGB – beta – important immunosuppression Adaptive imunity – immune response is process; immune reactions are once generate antibodies or cytokines or cells, have action to target – multiple layers of self-tolerance Opsonisation – antibody bind to macrophage Fc receptor Crosstalk between the two – mutually help Emphasize multiple layers – Cells involved in cellmediated specific immune responses APC – non professional lead to tolerance; professional lead to immunity T lymphocytes – Th17 – inflammatory helper cells Significant T suppressive cells – called regulatory cells – could be positive or negative – Professional APC – different morphology Tolerance vs immunity Role of APC If function too high, lead to autoimmunity If resting antigen presenting cell, induce tolerance For anti-microorganisms, and anti-tumour – help lead into tolerance – decrease inflammatory disease How does APC become mature Triggered by TLR or adhesion molecues? Clear evidence that suggest molecules important In 2006, California San Fran University – observed beta 8 integrins deficient animals develop very severe autoimmune disease – publish Nature 2007 – Alpha V beta 8 expressed on DC play important role in autoimmune response Gamma globulin – IvIg – treat autoimmune disease – if incubate with DC – let DC decrease immune response to control autoimmune disease to treat patient – Maturation of DC could affect immune response as well as immune tolerance Naïve T cells that recognize Ag on the surface of APC and receives CTL cells could target virus infected cells or CTL cells could target the beta cell in the pancreas islets – lead to type 1 diabetes – already have CTL cells – important for immune surveillance to target immune surveillance cell – TH1 and Th2 immune response important Th1 – role for ar
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