Immunology System.docx

Immunology is the study of the immune system and the mechanisms that provide immune defence. Immunology is the branch of science dealing with the components of the immune system, immunity from disease, the immune response, and immunologic techniques of analysis. The immune system comprises organs, t...

Immunology is the study of the immune system and the mechanisms that provide immune defence. Immunology is the branch of science dealing with the components of the immune system, immunity from disease, the immune response, and immunologic techniques of analysis. The immune system comprises organs, tissues, cells and molecules that provide immune defence against microorganisms The immune system distinguishes between SELF and NONSELF Components of the immune system can be NONSPECIFIC or SPECIFIC NONSPECIFIC immunity is available immediately-first line of defence to any NONSELF material INFLAMMATION is an example of nonspecific defence ACUTE PHASE RESPONSE is a nonspecific response to infection The immune system consists of organs, tissues, cells and molecules that have developed to protect the body from damage caused by microorganisms – (bacteria, fungi, viruses and parasites). The immune system distinguishes between cells and macromolecules that are found in our bodies cells, known as SELF, and those that are not present in our bodies (known as foreign or nonself). The different components of the immune system can be classified as NONSPECIFIC or SPECIFIC. Nonspecific immunity provides the first line of defence and is available immediately to any nonself material. Inflammation is an example of nonspecific defence-as you can see in the picture, it is a rapid immediate response to tissue damage for example when a splinter enters the skin-inflammation is seen as a red swelling at the site of the injury and results from: -increased blood supply to the injured area -increased permeability of the blood vessels -movement of white blood cells from the blood vessels into the tissues ACUTE PHASE RESPONSE is a nonspecific, relatively rapid response to infection, and involves production of serum molecules such as C-reactive protein. The defensive protection is performed by white blood cells (leucocytes-of which there are various types) and some additional cells (accessory cells-these will be the subject of the next lecture. As well as molecules of the immune system which is the subject of the 3rd lecture. Chickenpox is a mild and common childhood illness that most children catch at some point. It causes a rash of red, itchy spots that turn into fluid-filled blisters. They then crust over to form scabs, which eventually drop off. Some children have only a few spots, but other children can have spots that cover their entire body. These are most likely to appear on the face, ears and scalp, under the arms, on the chest and belly, and on the arms and legs. Chickenpox (known medically as varicella) is caused by a virus called the varicella-zoster virus. It's spread quickly and easily from someone who is infected SPECIFIC immunity involves immune cells recognising specific parts of a microorganism (PROTEINS, GLYCOPROTEINS) SPECIFIC immunity takes longer to develop-not immediate SPECIFIC immunity is long-lasting because MEMORY cells are formed Immunity can be classed as HUMORAL or CELL-MEDIATED -HUMORAL involves the production of ANTIBODIES, important for extracellular microorganisms -CELL-MEDIATED involves the production of cells that kill or recruit other cells that kill infected cells, important for intracellular microorganisms Different parts of the immune system work together to provide protection against infectious disease such as chicken pox caused by virus (varicella zoster) SPECIFIC immunity involves particular types of immune cells recognising specific parts of a microorganism (PROTEINS, GLYCOPROTEINS) SPECIFIC immunity takes longer to develop from several days to several weeks, depending on whether you have previously been exposed to the microorganism SPECIFIC immunity is long-lasting because it produces memory cells which will quickly deal with a microorganism when you are subsequently exposed to it Immunity can be classed as HUMORAL or CELL-MEDIATED HUMORAL involves the production of ANTIBODIES, is effective against microorganisms that do not invade cells-this includes most bacteria and multicellular parasites. These are classed as extracellular microorganisms. However, some microorganisms enter cells-and once inside cells, antibodies cannot reach them. Cell mediated immunity is important for dealing with intracellular microorganisms. Cell mediated immunity involves the production of cells that kill or recruit other cells that kill infected cells. Cell mediated immunity effectively deals with intracellular microorganisms such as viruses and intracellular bacteria Different parts of the immune system work together to provide protection against infectious disease such as chicken pox caused by virus (varicella zoster) Chickenpox is a mild and common childhood illness which causes a rash of red, itchy spots that turn into fluid-filled blisters. Chickenpox is caused by a virus called the varicella-zoster virus. Autoimmune Diseases Immune system mistakenly attacks bodies own molecules (SELF) Treatments aimed at suppressing immunity or specific symptoms Systemic Lupus Erythematosus (lupus)-B lymphocytes produce antibodies against variety of self-molecules including histones and DNA. Symptoms: skin rashes, fever, arthritis and kidney malfunction When the immune system doesn’t work properly serious disease can result. Autoimmune diseases result when the immune system attacks the body’s own molecules-instead of targeting foreign molecules. Examples of autoimmune disease include insulin dependent diabetes mellitus –in which a type of immune cell called cytotoxic T cells destroy the insulin producing cells in the pancreas. Multiple sclerosis is another example- T cells target the myelin sheath surrounding neurons, causing serious neurological abnormalities. Lupus-characteristic facial rash is known as a butterfly rash Rheumatoid Arthritis-antibody mediated, resulting in damage, pain and inflammation of joints. Rheumatoid arthritis is a painful and debilitating autoimmune disorder that affects the joints. In rheumatoid arthritis the immune system attacks the lining of the joints (the synovium), causing inflammation and damage to the surrounding cartilage and bone. The joints – usually in the hands, wrists, knees or feet, on both sides of the body – swell and become painful, tender and stiff, especially early in the morning. About 10 per cent of people with rheumatoid arthritis will also develop lumps under the skin near the joints (called rheumatoid nodules)-as seen in this picture. As the condition progresses, especially if left untreated, the muscles around the joint waste away, the cartilage in the joint and the bone underneath erode away, and eventually the whole joint is filled with fibrous scar tissue until it freezes completely. It can leave the person with irreversibly damaged joints and deformities. RA it is more common in females, smokers, and onset usually occurs in people over the age of 35. Like other autoimmune diseases, rheumatoid arthritis tends to run in families. If you have a family member with the disease, your risk of also developing it is three to four times higher. Most people – but not all – with rheumatoid arthritis have antibodies called rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) in the blood. A blood test will detect these, but a small proportion of people never test positive for RF so it's not a definitive test for rheumatoid arthritis. Immunodeficiency Results when 1 or more components of immune system is missing Individuals have frequent infections Can be born with disease (primary) or acquire it during lifetime (secondary) Immunodeficiencies results when one or more components of the immune system are missing. This makes them susceptible to frequent and recurrent infections. Some immunodeficiency diseases you are born with, and result from genetic disease. SCID is a condition in which both b and t cells are absent or inactive and the individuals are at great risk from minor infections. Acquired Immuno Deficiency Syndrome (AIDS) Infection with the retroviruses HIV-1 or HIV-2 These viruses infect immune cells (which express CD4 including T cells and some antigen presenting cells) and disease progresses into AIDS Highly Active Anti-Retroviral Treatment (HAART) has had an enormous impact upon survival Still no effective vaccine available Retrovirus- A virus which uses the enzyme reverse transcriptase to copy its genome into the DNA of the host cells chromosomes. Many cancers in vertebrates are caused by retroviruses. AIDS is caused by the retroviruses HIV-1 or HIV-2 which infect cells expressing cd4 (special molecules on the cell surface) on some types of immune cells. After infection, some individuals develop a fever. Within weeks, special molecules called antibodies can be found in the blood-these antibodies are specific to parts of the virus, and the amount of virus present in the blood decrease. Within months of years, the number of one particular type of immune cell (T cell) gradually decreases over time, when these levels fall to a dangerously low level the individuals develop infections (to things that wouldn’t normally be problematic-this is known as opportunistic infections. Sh There is still no effective vaccine available despite extensive efforts during the last 30 years. In fact research being carried out to develop safe vaccines to prevent infection with the HIV viruses has led to many important scientific developments in the field of vaccines. One of the reasons for being unable to develop a suitable vaccine has been due to the virus being very smart-it develops lots of mutations (changes in RNA which means its constantly changing to escape detection. This is done deliberately by the virus to avoid detection by the immune system. However, to develop a vaccine which will be useful on a global scale, it needs to be specific (ie without lots of changes). 38.4 million people worldwide living with HIV at the end of 2021-25.6 million in WHO African Region 1.5 million people becoming newly infected with HIV in 2021 globally, fewer than in any year since 1990-60% of new cases were in WHO African Region The global HIV epidemic claimed 68% fewer lives in 2021 since its peak in 2004. All people living with HIV should start antiretroviral treatment as soon as they are diagnosed.  HIV responsible for 40.1 million deaths by July 2022 6.6 million deaths due to COVID-19 have been reported to WHO Immunological Disease: Allergies Exaggerated (hypersensitive) response to ALLERGENS 1 in 3 people are allergic. Genetic predisposition (ATOPY) Allergen-an antigen that causes an allergic reaction. Symptoms of allergies- swelling, hives (urticaria), runny eyes and nose (allergic rhinitis), anaphylactic shock (which can be treated with adrenaline which open airways) Treatments aimed at reducing immune response (antihistamines, anti-inflammatory) or desensitisation The human immune system is designed to attack anything it doesn't recognize. White blood cells recognize the body's tissues by looking for a set of antigens on the surface of each cell. The most important of these make up the major histocompatibility complex. When your immune system finds cells in your body that don't show the right MHC proteins, it tries to destroy them, which causes the donated organ to be rejected. Doctors test the MHC of potential organ donors to find the best match. The test focuses on six important MHC antigens, which can be identified from a long list that includes hundreds of possibilities. The chances of a perfect match are very small. The closer the match, the better the success rate for the transplant. Transplant rejection can also be lessened by use of immunosuppressant drugs after transplant. Transplant rejection involves several of the immunologic reactions. A major barrier to transplantation is the process of rejection, in which the recipient’s immune system recognizes the graft as being foreign and attacks it. One of the important goals of present-day immunologic research is successful transplantation of tissues in humans without rejection. Although the surgical expertise for the transplantation of skin, kidneys, heart, lungs, liver, spleen, bone marrow, and endocrine organs is now well in hand, it outpaces thus far the ability to confer on the recipient permanent acceptance of foreign grafts. Mechanisms Involved in Rejection of Kidney Grafts As stated above, graft rejection depends on recognition by the host of the grafted tissue as foreign. The antigens responsible for such rejection in humans are those of the HLA system. Because HLA genes are highly polymorphic, any two individuals (other than identical twins) will express some HLA proteins that are different. Thus, every individual will recognize some HLA molecules in another individual as foreign (allogeneic) and will react against these. This reaction is the basis of rejection of grafts from one individual to another. Rejection is a complex process in which both cell-mediated immunity and circulating antibodies play a role; moreover, the relative contributions of these two mechanisms to rejection vary among grafts and are often reflected in the histologic features of the rejected organs. T Cell-mediated rejection The critical role of T cells in transplant rejection has been documented both in humans and in experimental animals. T cell-mediated graft rejection is called cellular rejection, and it is induced by two mechanisms: destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated CD4+ helper cells. The recipient’s T cells recognize antigens in the graft (the allogeneic antigens, or alloantigens) by two pathways, called direct and indirect. In the direct pathway, T cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface of an antigen-presenting cell in the graft. It is believed that dendritic cells carried in the donor organs are the most important immunogens because they not only richly express class I and II HLA molecules but also are endowed with costimulatory molecules (e.g., B7-1 and B7-2). The T cells of the host encounter the dendritic cells either within the grafted organ or after the dendritic cells migrate to the draining lymph nodes. Both the CD4+ and the CD8+ T cells of the transplant recipient are involved in this reaction. CD8+ T cells recognize class I HLA antigens and differentiate into mature CTLs. This process of CTL differentiation is complex and incompletely understood. It appears to be dependent on the release of cytokines, such as IL-2, from CD4+ helper cells and CD40 ligand on the helper cells activating antigen-presenting cells to promote the differentiation of CTLs. Once mature CTLs are generated, they kill the grafted tissue by mechanisms already discussed. The CD4+ helper T-cell subset is triggered into proliferation and differentiation into TH1 effector cells by recognition of allogeneic class II molecules. As in delayed hypersensitivity reactions, cytokines secreted by the activated CD4+ T cells cause increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages), and activate the macrophages, resulting in graft injury. The direct recognition of allogeneic MHC molecules seems paradoxical to the rules of self-MHC restriction: If T cells are normally restricted to recognizing foreign peptides displayed by self-MHC molecules, why should these T cells recognize foreign MHC? Such recognition has been explained by assuming that allogeneic MHC molecules, with their bound peptides, resemble, or mimic, the self-MHC-foreign peptide complexes that are recognized by self-MHC-restricted T cells. The structural basis of such mimicry is not entirely clear. In the so-called indirect pathway of allorecognition, recipient T lymphocytes recognize antigens of the graft donor after they are presented by the recipient’s own antigen-presenting cells. This process involves the uptake and processing of MHC molecules from the grafted organ by host antigen-presenting cells. The peptides derived from the donor tissue are presented by the host’s own MHC molecules, like any other foreign peptides. Thus, the indirect pathway is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens. The indirect pathway generates CD4+ T cells that enter the graft and recognize graft antigens being displayed by host antigen-presenting cells that have also entered the graft, and the result is a delayed hypersensitivity type of reaction. However, CD8+ CTLs that may be generated by the indirect pathway cannot directly recognize or kill graft cells, because these CTLs recognize graft antigens presented by the host’s antigen-presenting cells. Therefore, when T cells react to a graft by the indirect pathway, the principal mechanism of cellular rejection may be T-cell cytokine production and delayed hypersensitivity. It is postulated that the direct pathway is the major pathway in acute cellular rejection, whereas the indirect pathway is more important in chronic rejection. However, this separation is by no means absolute. Antibody-mediated rejection Although there is little doubt that T cells are pivotal in the rejection of organ transplants, antibodies evoked against alloantigens in the graft can also mediate rejection. This process is called humoral rejection (antibody-mediated rejection), and it can take two forms. Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient. Such antibodies may be present in a recipient who has already rejected a kidney transplant. Multiparous women who develop anti-HLA antibodies against paternal antigens shed from the foetus may also have preformed antibodies to grafts taken from their husbands or children, or even from unrelated individuals who share HLA alleles with the husbands. Prior blood transfusions can also lead to presensitization because platelets and white blood cells are rich in HLA antigens and donors and recipients are usually not HLA-identical. When preformed antidonor antibodies are present, rejection occurs immediately after transplantation because the circulating antibodies react with and deposit rapidly on the vascular endothelium of the grafted organ. Complement fixation occurs, resulting in thrombosis of vessels in the graft, and ischemic death of the graft. With the current practice of cross-matching, that is, testing recipient’s serum for antibodies against donor’s cells, hyperacute rejection is no longer a significant clinical problem. In recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens of the donor may evoke antibodies. The antibodies formed by the recipient may cause injury by several mechanisms, including complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity. The initial target of these antibodies in rejection appears to be the graft vasculature. Thus, antibody-dependent, or acute humoral rejection, is usually manifested by a vasculitis, sometimes referred to as rejection vasculitis. Morphology of Rejection Reactions. On the basis of the morphology and the underlying mechanism, rejection reactions are classified as hyperacute rejection, acute rejection, and chronic rejection. Types of rejection reaction  hyperacute rejection acute rejection humoral acute rejection cellular acute rejection  chronic rejection chronic humoral rejection (antibody-mediated rejection) People can become immune either by being exposed to the infectious agent directly or by receiving a vaccine. Vaccination is immunization with a vaccine. Immunotherapy: Treatment to stimulate or restore the ability of the immune (defence) system to fight infection and disease. Biological therapy is thus any form of treatment that uses the body's natural abilities that constitute the immune system to fight infection and disease or to protect the body from some of the side effects of treatment. Immunotherapy (also called biological therapy or biotherapy) often employs substances called biological response modifiers (BRMs). The body normally produces low levels of BRMs in response to infection and disease. Large amounts of BRMs can be made in the laboratory to treat cancer, rheumatoid arthritis, and other diseases. Immunoassays Test used to detect presence/quantity of a substance based on its ability to act as an antigen or antibody (ANTIGEN-any molecule that can be recognized by B or T cells ANTIBODY-protein produced after contact with antigen) Immunoassays routinely used worldwide in hospitals and research labs Role of immune system is to protect the body from damage caused by microorganisms. This is achieved by white blood cells (AKA Leukocytes) and various accessory cells found throughout the body particularly in the lymphoid organs. Lymphoid organs include BONE MARROW, THYMUS, SPLEEN, and mucosa-associated lymphoid tissue Lymphoid organs are strategically placed to protect different areas of the body from infection Cells move between the tissues via the bloodstream and lymphatic system. Whilst they do this, they interact with each other to generate coordinated immune responses, in order to eliminate pathogens or minimise the damage they cause. Different types of immune cells- lymphocytes, antigen-presenting cells, phagocytes, accessory cells. Lymphocytes Important cells controlling the immune response Achieve this by recognizing molecules produced by pathogens Can recognise molecules on cells of body, but do not normally react against the body’s own tissues (unless in autoimmune disease) Molecules recognized by lymphocytes are called ANTIGENS Recognize foreign material by specific cell-surface antigen receptors The receptors are extremely diverse so that they can recognize any potential molecule encountered during individual’s lifetime Each lymphocyte makes only 1 type of antigen receptor i.e., they are specific (part of ADAPTIVE IMMUNITY) 3 types of lymphocytes are: -B cells/B lymphocytes which produce ANTIBODIES -T cells/T lymphocytes which have several roles (see below) -Natural killer cells role in antiviral defence (much less common than B and T cells) Function of T cells are: -Helping B cells to produce antibody -Recognizing and destroying cells that have become infected with intracellular pathogens -Activating phagocytes to destroy pathogens that they have taken up -Regulating the level and quality of the immune response Phagocytes Ingest (PHAGOCYTOSE) pathogens, antigens and cell debris and break them down Antibodies and other recognition molecules help in this process Phagocytes include blood monocytes, macrophages and neutrophils Macrophages can also process and present antigens so that they can be recognized by T cells Accessory Cells -Accessory cells include granulocytes (eosinophils and basophils), mast cells, platelets and antigen-presenting cells (APCs) -APCs include B cells, macrophages, dendritic cells* (*most important) in presenting antigen to NAÏVE T cells