Lecture 1 / 2011-2012 Professor Dr. Zainalabideen A. Abdulla, College of Medicine DTM&H. (Liverpool), Ph.D. (Oxford), FRCPath. (U.K) IMMUNOLOGY THE IMMUNE SYSTEM The main function of the immune system is to protect the host from pathogen and to minimize damage to self tissue. The immune system was discovered around the end of the 19th century. Therefore, immunology is relatively a new science.
Definition of Immunity:Immunity was derived from the Latin word “Immunos” which means exempted from tax. The tax is the “disease". So, to be immune from a disease (protected), it means exempted from that disease. Example: a child early in life commonly gets measles; when exempted from it , the child is immune (protected).
The FIRST aim of immunity (immune system ) is the PROTECTION (resistance) to diseases. Infectious diseases were quite common previously. They were the major causes of death. Hence, the microbiologists were the first people who worked in the field of immunity aiming for the protection from those diseases. Example: Edward Jenner was the first scientist who worked in the field of protection against small pox. He use cow pox to protect a child from small pox. He introduced the word Variolation (now is called vaccination).
Spectrum of immunology Protection (resistance) 2. Hypersensitivity 3. Autoimmunity 4. Immunodeficiency
Protection (resistance) to infection is the first priority of the immune system. Humans are in continuous associations with microorganisms, including those that readily colonize the body surfaces (The Bacterial Flora of Humans). It is relatively rare that these microorganisms cause damage to their host. In part, this is due to the effectiveness of the host defense mechanisms, which restrict invasion by normal flora (some of which may be potential pathogens), and which defend against non-indigenous microorganisms that are overt pathogens.
II. Hypersensitivity: Some times the immune reaction (response) results in harmful out come (tissue damage), which is called Hypersensitivity. There are four types of HYPS (I, II, III, & IV) : Type I : Immediate Type II : Cytotoxic Type III: Immune-Complexes Type IV: Delayed (cell-mediated)
III. Auto-immunity: The immune system reacts against the body itself (auto-reaction)which is called Auto-immune response. The diseases that result from such a response are called auto-immune diseases. Normally the immune system does NOT react against the body itself by a mechanism which is named Tolerance (state of unresponsiveness).
HLA (MHC) The immune system learns early in life (development) how to recognize self from non-self tissues or cells. This is mediated mainly via a system which is called HLA (Human Leucocyte Antigens) or is also called MHC (Major Histocompatibility Complex).
The break down of self tolerance was first reported by Paul Ehrich(1854-1915) as Horror Autotoxicus (now called Auto-immune diseases). Self Tolerance Break-down Auto-immunity
IV. Immunodeficiency states (diseases): Dysfunction or deficiency of the immune response leads to a wide variety of diseases involving every organ system in the body. The aim of this course is to give fundamental understanding of the immune system and how it contributes to human diseases.
Branches of immunology: Basic Immunology Clinical immunology Immunochemistry Immunopathology Immunogenetic Immunohaematology Immuno-Oncology Immunodeficiency Allergy and Hypersensitivities. Part of different medical fields.
Protection (resistance): The immune system can function in TWO major ways (types of immunity): 1. Non-specific immunity (Innate) 2. Specific immunity (Adaptive) The main differences between the two types are: The innate immunity is NOT specific (recognizes generic microbial structures), while the adaptive immunity is specific (antigen-specific responses). The innate immunity is the first line of defense (immediately mobilized; in minutes), while the adaptive immunity is the second line of defense (slow response; in days).
3. The adaptive immunity is characterized by specific recognition capability which is NOT applicable in innate immunity. 4. The adaptive immunity generates MEMORY cells (remember), while the innate immunity does NOT produce such cells. 5. Innate immunity is genetically encoded and produces identical responses in all individuals, while specific immunity is acquired as an adaptive response to exposure to antigens. 6. Innate immunity is present in both invertebrates and vertebrates, while adaptive immunity is only present in vertebrates.
Coordination between types of immunity: We are constantly being exposed to infectious agents and yet, in most cases, we are able to resist these infections. It is our immune system that enables us to resist infections. The immune system is composed of two major subdivisions, the innate or non-specific immune system and the adaptive or specific immune system. The innate immune system is our first line of defense against invading organisms while the adaptive immune system acts as a second line of defense and also affords protection against re-exposure to the same pathogen. Each of the major subdivisions of the immune system has both cellular and humoral (blood) components. In addition, the innate immune system also has anatomical features that function as barriers to infection.
Protection is against what? Against foreign substances which are called ANTIGENS. These antigens could be bacteria, viruses, fungi , parasites, cells tissues, chemicals , drugs or food. The numbers of antigens in nature are up to trillions. Part of the organisms are also antigens. Memory cells remember these antigens.
Specific immunity (Adaptive): This type of immunity is characterized by: 1. Specific recognition of the antigens. 2. Effecter mechanisms which are of TWO types: A. Humoral: by antibodies and complement. Antibodies : Are protein molecules that react specifically with antigens. Complement: series of enzymes or active substances that could result in lyses of the target cell or other secondary reactions. The classical complement pathway (C1-C9) is part of the specific immunity, while the alternative (properdin) pathway (C3-C9) is part of the non-specific immunity.
Lymphocytes: Lymphocytes originate from BONE MARROW. 1. B-lymphocytes (B-cells),transform to plasma cells which produce antibodies. These antibodies are of FIVE classes (IgG, IgA, IgM, IgD, and IgE). B = Bursa of Fabricius (Hind gut lymphoid organ in birds). 2. T-Lymphocytes (T-cells), see below. T = Thymus developed cells. 3. Natural-Killer Lymphocytes (NK cells), which are large granular lymphocytes.
B. Cellular Immunity: This type of immunity is mediated by T-cells. These T- cells are of TWO types: A. T-helper (CD4); they could be Th0, Th1, Th2, Th9, Th17, Treg, NKT, and TFH B. T-cytotoxic (CD8) CD = Cluster of Designation (Differentiation). Used with monoclonal antibodies(MCA). MCA = Antibodies prepared in the laboratory by tissue culture. All lymphocytes mediate their functions by CYTOKINES which are chemical messages(e.g., Interleukins as IL-1, 2, 3 …etc).
Non-Specific Immunity (Innate): Innate immunity is the first front of defense of the body. It has TWO lines: 1. The First line of Innate Immunity; which has the following 3 mechanisms: A. Anatomical and physiological barriers Including the skin, mucous membranes (400 sq. m.), hair, cilia, sneezing, cough, and blinking of the eyes. Also, mucous secretions trap many organisms.
Anatomic Barriers Skin (physical barrier, low pH due to lactic and fatty acids) epidermis - thin outer layer containing tightly packed epidermal cells and keratin (water-proofing) completely renewed every 15-30 days. dermis - thicker inner layer contains sebaceous glands associated with hair follicles - produce sebum which consists of lactic and fatty acids maintaining a pH 3-5. Mucous membranes (ciliated epithelial cells; saliva, tears and mucous secretions) - GI, urogenital, respiratory tracts - collectively represents a huge surface area. Physiologic Barriers Temperature - normal body temperature inhibits growth of most microorganisms. Elevated body temperature (fever) can have a direct effect on pathogenic microorganisms. pH - low pH of stomach, skin, & vagina (inhibits microbial growth) Oxygen tension
B. Chemical Barriers; as sweat, and sebaceous secretions of the skin. These substances provide acidity (by acidic pH & fatty acids) to the skin and prevent m.o. from growth. Also, the hydrolytic enzymes in the saliva and HCl of the stomach are other chemical barriers. The gastric juice is a major barrier against invading microbes. Suppression of this juice by disease or drugs (as H2-blockers) can increase the risk of infections via the gastro-intestinal tract. The proteolytic enzymes of the intestine (as pepsin) have similar bactericidal actions. Furthermore, substances called Lysozymes which are present in the tears, saliva, vaginal secretion, and on the skin can attach to m.o. like bacteria and cause hydrolyses of peptidoglycan of the cell wall ,then destruction of the bacteria. Finally, the Acidic pH of the vagina which is maintained by the Lactobacilli (bacteria) can prevent many m.o. from colonizing the female genital tract.
C. Natural bacterial flora: Many m.o. are present normally in the mouth, large intestine (small intestine is sterile), vagina, external ears, nose, or on the skin. These m.o. prevent other m.o. from colonizing these areas by competition for nutrients and production of enzymes or growth suppressor materials as Colicin (produced by enteric bacilli). Inhibition or killing of the natural flora as could happen by using antibiotics might result in superinfections (added infections).
2. The second line of innate immunity: This line of defense is located deeper in the body than the first line. It has the following items: I. Bactericidal (destructive or killing) substances which are toxic to many bacteria and include 4 categories: A. Lysozymes which are present in all body fluids. B. Alternative complement (Properdin) pathway which start from C3 and may end up to C9. Note: The classical complement pathway (C1-C9) is part of the adaptive immunity (specific immunity).
C. Acute phase proteins: These are substances that increase in response to inflammation and include : C-reactive protein (CRP), Mannose binding proteins or lectins (MBL), fibrinogen, ceruloplasmin, alpha-1 antitrypsin and alpha 2 macroglobulin. These substances are synthesized in the LIVER in response to IL-1, IL-6 and tumour necrosis factor (TNF) which are produced by macrophages. They can function to : 1. enhance host resistance. 2. minimize tissue injury . 3. promote the resolution & repair of inflammatory lesions. Example : CRP activates complement & enhances Phagocytosis via C3b ( immune adherence / opsonization). Phagocytes IL1,6 & TNF Liver APP
D. Interferons (INF): These are a family of proteins which are important in defense against viral infections. They are released from virus-infected cells and protect other non-infected cells from the same virus and other viruses. They are of THREE types: 1. INF-alpha (from leucocytes). 2. INF-Beta (from fibroblasts and most other cells). 3. INF-gamma (from T-cells). The INFs have THREE functions: 1. Anti-viral activity. 2. Immunoregulatory (e.g.,INF-gamma stimulates NK cells). 3. Anti-proliferative (anti-cancer).