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“We shall fight!” What you need to know about the immune system - for beginners and more advanced INGID Meeting 2012 Ann Gardulf, RN, PhD Associate Professor.

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Presentation on theme: "“We shall fight!” What you need to know about the immune system - for beginners and more advanced INGID Meeting 2012 Ann Gardulf, RN, PhD Associate Professor."— Presentation transcript:

1 “We shall fight!” What you need to know about the immune system - for beginners and more advanced INGID Meeting 2012 Ann Gardulf, RN, PhD Associate Professor Section of Clinical Immunology, Karolinska Institutet,Stockholm

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3 The Human Immune Defence Pluripotent stem cell T lymphocytesB lymphocytes Lymphocytes Monocytes/ Macrophages Granulocytes Neutrophils Eosinophils Basophils Leucocytes Thrombocytes Erythrocytes Y Y Y Y Antibodies IgG - IgG subclasses IgA IgM IgD IgE Copyright Ann Gardulf

4 The Human Immune Defence Pluripotent stem cell T lymphocytesB lymphocytes Lymphocytes Monocytes/ Macrophages Granulocytes Neutrophils Eosinophils Basophils Leucocytes Thrombocytes Erythrocytes Y Y Y Y Antibodies IgG - IgG subclasses IgA IgM IgD IgE Copyright Ann Gardulf

5 Main areas for the lecture  What are antibodies/immunoglobulins?  The structure of antibodies  Antibody-antigen binding  The production of antibodies  The function of antibodies in our immune defence  What can go wrong?  What diseases are treated with antibodies (today)? Copyright Ann Gardulf

6 What are antibodies/immunoglobulins? Copyright Ann Gardulf

7 What are antibodies/immunoglobulins?  Large proteins with an ability to bind to all structures/particles that our immune defence identifies as an enemy (=antigen). Copyright Ann Gardulf

8 What are antibodies/immunoglobulins?  Large proteins with an ability to bind to all structures/particles that our immune defence identifies as an enemy (=antigen).  The antibodies are produced by the B-cells/B- lymphocytes. Copyright Ann Gardulf

9 What are antibodies/immunoglobulins?  Large proteins with an ability to bind to all structures/particles that our immune defence identifies as an enemy (=antigen).  The antibodies are produced by the B-cells/B- lymphocytes.  An active B-cell is called plasma cell and they are able to produce large amounts of antibodies every second. Copyright Ann Gardulf

10 What are antibodies/immunoglobulins?  Large proteins with an ability to bind to all structures/particles that our immune defence identifies as an enemy (=antigen).  The antibodies are produced by the B-cells/B- lymphocytes.  An active B-cell is called plasma cell and they are able to produce large amounts of antibodies every second.  Some plasma cells will develop into memory cells and are very important for the development of immunity. Copyright Ann Gardulf

11 What is the task for our antibodies? Copyright Ann Gardulf

12 What is the task for our antibodies?  To help in the protection against (harmful) antigens. Copyright Ann Gardulf

13 What is the task for our antibodies?  To help in the protection against (harmful) antigens.  The antibodies cannot kill antigens themself. Instead they act as a mediators. Copyright Ann Gardulf

14 What is the task for our antibodies?  To help in the protection against (harmful) antigens.  The antibodies cannot kill antigens themself. Instead they act as a mediators.  The antibodies will identify and mark what they find as an antigen (”signal flag”). Copyright Ann Gardulf

15 What is the task for our antibodies?  To help in the protection against (harmful) antigens.  The antibodies cannot kill antigens themself. Instead they act as a mediators.  The antibodies will identify and mark what they find as an antigen (”signal flag”).  The variable part of the antibody will bind to the antigen at thereby signal that this antigen must be eliminated. Copyright Ann Gardulf

16 What is the task for our antibodies?  To help in the protection against (harmful) antigens.  The antibodies cannot kill antigens themself. Instead they act as a mediators.  The antibodies will identify and mark what they find as an antigen (”signal flag”).  The variable part of the antibody will bind to the antigen at thereby signal that this antigen must be eliminated.  The constant part of the antibody will stand for the choice how the elimination will take place. Copyright Ann Gardulf

17 What does an antibody (IgG) look like? Copyright Ann Gardulf

18  It comprises of 4 protein chains (polypeptide chains): two heavy chains and two light chains. The chains are being hold together by disulphide bonds. What does an antibody (IgG) look like? Copyright Ann Gardulf A=heavy chains B=light chains =disulphide bonds

19  The light chains consist of two domains and the heavy chains of four domains. What does an antibody (IgG) look like? Copyright Ann Gardulf

20  The chains/domains are closely linked and form a very compact protein structure What does an antibody (IgG) look like? Copyright Ann Gardulf Heavy chain Light chain

21  The area in-between domain two and three on the heavy chain is called the ”hinge region”.  In this region the antibody is moveably.  The antibody can use this mechanism to adjust the distance between the two arms and thereby better adjust to the antigen. What does an antibody (IgG) look like? Copyright Ann Gardulf

22 What does an antibody (IgG) look like? Copyright Ann Gardulf

23  The ends of both the heavy and the light chains are called the variable parts of the antibody.  It is the variable regions of the antibody that will bind to the antigen.  The rest of the antibody is called the constant region. What does an antibody (IgG) look like? Copyright Ann Gardulf Variable regions Constant region

24 The antigen-antibody binding process  Each variable region (the antigen-binding region) is in reality consisting of nine protein strings: beta strings. Copyright Ann Gardulf Variable regions Constant region

25 The antigen-antibody binding process  Each variable region (the antigen-binding region) is in reality consisting of nine protein strings: beta strings.  Parts of these protein strings are so called hyper-variable regions and have been named CDR1, CDR2 and CDR3. Copyright Ann Gardulf Variable regions Constant region

26  The CDR1, CDR2 and CDR3 form loops at the far end of the variable part of the antibody. The antigen-antibody binding process Copyright Ann Gardulf

27  We normally say that antibodies have ”binding sites” but this is not really correct. The antigen-antibody binding process Copyright Ann Gardulf

28  We normally say that antibodies have ”binding sites” but this is not really correct.  Instead, the hyper-variable regions form a rift with a wrinkled surface that will bind to the antigen. The antigen-antibody binding process Copyright Ann Gardulf

29 The production of antibodies Copyright Ann Gardulf

30 The production of antibodies  Antibodies are produced by the B-cells/B-lymphocytes  Before being activated and turning into a plasma cell, the B-cell/B-lymphocyte has IgM antibodies on its surface and use them as receptors to detect and identify antigens (”feelers”). Copyright Ann Gardulf

31  The B-cell/B-lymphocyte needs signals to turn into a plasma cell: Copyright Ann Gardulf The production of antibodies T-cell independent respons 1. Contact with and binding to the antigen 2. Cytokine signal

32  The B-cell/B-lymphocyte need three signals to turn into a plasma cell: Copyright Ann Gardulf The production of antibodies T-cell independent responsT-cell dependent respons 1. Contact with and binding to the antigen 2. Interaction with T-lymphocytes (CD4+) (large protein structures, e.g. virus) 2. Cytokine signal3. Cytokine signal Proteins - better immunity

33 Copyright Ann Gardulf The production of antibodies

34  During the initial antibody response, the antibodies are almost exclusively of IgM type. Copyright Ann Gardulf The production of antibodies

35  During the initial antibody response, the antibodies are almost exclusively of IgM type.  As the defence develops, the constant parts of the antibodies are changes (class switching) so that the B-cell/B-lymphocyte now produce IgG, IgA or IgE (what is needed). Copyright Ann Gardulf The production of antibodies

36  During the initial antibody response, the antibodies are almost exclusively of IgM type.  As the defence develops, the constant parts of the antibodies are changes (class switching) so that the B-cell/B-lymphocyte now produce IgG, IgA or IgE (what is needed).  Observe that the successful variable parts remain! Copyright Ann Gardulf The production of antibodies

37  The knowledge that IgM is the first antibody that our B-cells/B-lymphocytes produce when we get infected is a knowledge that we use for interpreting serologies. Copyright Ann Gardulf The production of antibodies

38  The ”cookbook” how to produce antibodies is divided into different ”chapters”, i.e. one chapter for each antibody class. Copyright Ann Gardulf The production of antibodies

39  The ”cookbook” how to produce antibodies is divided into different ”chapters”, i.e. one chapter for each antibody class.  These ”chapters” are in reality genes and it is the genes that activate the change of class (e.g. from IgM to IgG). Copyright Ann Gardulf The production of antibodies

40  The ”cookbook” how to produce antibodies is divided into different ”chapters”, i.e. one chapter for each antibody class.  These ”chapters” are in reality genes and it is the genes that activate the change of class (e.g. from IgM to IgG).  The genes look like a ”pearl necklace”. First in line is the gene coding for IgM, thereafter IgD, the different types of IgG, IgE and IgA. Copyright Ann Gardulf The production of antibodies

41  In front of the gene is a so called ”switch-box” (the red ”points”): When the B-cell/B-lymphocyte changes production of class, two of the switch-boxes are brought together and the superfluity is cut away by an enzyme. Genes for the variable part IgM IgD IgGs different genes IgE IgA Copyright Ann Gardulf The production of antibodies

42  This is the way it happens: IgM IgD IgGs different genes IgE IgA Copyright Ann Gardulf The production of antibodies Genes for the variable part

43 The function of the antibodies Copyright Ann Gardulf

44 The function of the antibodies Copyright Ann Gardulf Amount in blood Class Very little Class Amount Basic Structure Functions Comments in blood structure secretory Unclear Protection against infections Activate the complement defence Protection against infections Make up our defence of the mucosa membranes Protection against infections Fc region identified by Fc receptors on all phagocytising cells (e.g. neutrophils) Activate the complement defence Protection against infections (parasites) Also involved in allergies. The only ab class passing placenta J=joining

45 1. Stimulate phagocytosis IgG works as opsonises (”spices”) and stimulates the neutrophils to phagocytosis. The neutrophils will thereafter destroy the antigen. The function of the antibodies Copyright Ann Gardulf

46 1. Stimulate phagocytosis IgG works as opsonises (”spices”) and stimulates the neutrophils to phagocytosis. The neutrophils will thereafter destroy the antigen. 2. Activation of the complement defence Activation of the proteins that build up the so called Membrane Attach Complex (MAC) that can destroy the wall of bacterias. IgM is the antibody that best activates the complement defence, thereafter IgG. The function of the antibodies Copyright Ann Gardulf

47 3. Killing of (viral) infected cells Once IgG has attached to the surface of a (viral infected) cell in body, CD8+ is able to kill the infected cell (ADCC - Antigen Dependent Cellular Cytotoxicity). The function of the antibodies Copyright Ann Gardulf

48 3. Killing of (viral) infected cells Once IgG has attached to the surface of a (viral infected) cell in body, CD8+ is able to kill the infected cell (ADCC - Antigen Dependent Cellular Cytotoxicity). 4. Neutralizing (“blocking”) of micro-organisms/toxins Antibodies can block antigens by holding on to them. IgA protect the mucosal surface by blocking micro-organisms; IgG block virus, toxins to reach their target cells. The function of the antibodies Copyright Ann Gardulf

49 5. Decreased mobility of the antigens Once antibodies have reached an antigen and holds on to it, it becomes much more difficult for the antigen to move and spread in our bodies. The function of the antibodies Copyright Ann Gardulf

50 What can go wrong? Copyright Ann Gardulf

51  A lot (if not everything) !  From the production of B-cells/B-lymphocytes in the BM, to the maturation of the cells with its antibody production including the capacity of keeping the variability of antibodies and the class changes. What can go wrong? Copyright Ann Gardulf

52  A lot (if not everything) !  From the production of B-cells/B-lymphocytes in the BM, to the maturation of the cells with its antibody production including the capacity of keeping the variability of antibodies and the class changes.  Any mistake – and we have some sort of antibody deficiency. What can go wrong? Copyright Ann Gardulf

53 Different causes to primary and secondary antibody deficiencies Smith et al., Läkartidningen 1992 Copyright Ann Gardulf

54 What can go wrong? Copyright Ann Gardulf Type of PID Prevalence B-CELL DEFECTS XLA1: Hyper-IgM-syndrome1: CVID1: – 1: IgA-deficiency1:600 IgG-subclass deficiencies1:500 ? T-CELL DEFECTS DiGeorge syndrome1:4 000 COMBINED B AND T-CELL DEFECTS SCID1: – 1: Ataxia-telangiectasia1: GRANULOCYTE DEFECTS Chronic granulomatous disease (CGD)1: COMPLEMENT DEFECTS C2-deficiency1: C1-inhibitor deficiency1: Notarangelo et al., JACI, 2010 Klinisk immunologi, kap 3, Studentlitteratur, 2012

55  Treatment with so called biological products are becoming more and more common  Polyclonal antibody products, e.g. gammaglobulin (IgG)  Monoclonal antibodies What diseases are treated with IgG? Copyright Ann Gardulf

56 Gammaglobulin (IgG) – examples of indications  Primary immunodeficiencies (replacement therapy: IVIG, SCIG, IMIG)  Secondary immunodeficiencies (replacement therapy: IVIG, SCIG)  Autoimmune diseases (immunomodulating effects) -ITP -Kawasaki’s disease -Guillan-Barrés syndrome -Multifocal motoric neuropathy (MMN) Off-label (60%) -Myastenia gravis -MS -Dermatomyositis In the future? - Alzheimer’s disease Copyright Ann Gardulf What diseases are treated with IgG?

57  Antibodies are a very important part of our immune defence  The production of antibodies in our bodies also constitute a threat as they wrongly can cause autoimmune diseases and/or allergies.  The knowledge about antibodies are important for o Diagnostic procedures o Treatments  Antibodies are a future area for treatments, research and clinical development - also for nurses! To conclude Copyright Ann Gardulf

58 Thank you very much! Copyright Ann Gardulf


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