UNIT OBJECTIVES Review following concepts of immune response Components of immune response Humoral versus cell mediated immunity Antigen processing presentation & recognition Immediate and delayed hypersensitivity Discuss disorder of immune response including; AIDS (Acquired Immunodeficiency syndrome) Hypersensitivity (allergies) Discuss the epidemiology, pathogenesis & clinical manifestation of HIV infection. Discuss the pathophysiology of different types of hypersensitivity Type I, Type II, Type III & Type IV Immune system body protects itself from infectious organisms & other harmful invaders through an elaborate net work of safeguards called host defense system. This system has three lines of defense: first line of defense: physical and chemical barriers to infection Second line of defence: inflammatory response third line of defense, adaptive immunity Structures of immune system Body’s 05 structures make up immune system: 1. Bone Marrow ( Production & Development of B-cells, then migrate to the lymph nodes) 2. Lymph Nodes (distributed along lymphatic vessels throughout body, filter lymphatic fluid,remove bacteria & toxins from circulation) 3. Thymus (secretes a group of hormones that enable lymphocytes to develop into mature T cells.) 4. Spleen (reservoir for blood, clear cellular debris process hemoglobin, macrophages) 5. Tonsils (lymphoid tissue and also produce Immunity • means protection from disease and, more specifically, infectious disease. Immune Response • Collective, coordinated response of cells & molecules of the immune system. Antigens, or immunogens, • are substances/ molecules that are foreign to the body but when introduced trigger the production of antibodies by B lymphocytes leading to ultimate destruction of invader. Types of Immunity Body’s defense against microbes is mediated by two types of immunity: 1. Non-specifc (or innate) immunity 2. Specifc (acquired/ Adaptive) immunity. Both types of immunity are members of an integrated system in which numerous cells and molecules function cooperatively to pro tect the body against foreign invaders. Innate/ Nonspecific Immunity first line of defense against microbial agents can distinguish between self and nonself through recognition of conserved broad patterns on microbes. include physical & chemical barriers, complement complex, and cells such as phagocytes (cells programmed to destroy foreign cells, such as bacteria) and natural killer lymphocytes. Continue Physical barriers include skin and mucosal membranes. Mechanical barriers Actions involving cilia, coughing, sneezing and tears Chemical barriers, include tears, breast milk, sweat, saliva, semen, acidic secretions including stomach acid. Most of these secretions contain either bactericidal enzymes such as lysozyme, or antibodies. Blood cells include leucocytes (WBC) & thrombocytes (platelets) white cells involved Phagocytic cells as: neutrophils, eosinophils, monocytes and macrophages Mediator/ helper cells as basophils & mast cells. Adaptive Immunity • Involves a complex series of interactions b/w components of immune system & antigens of a foreign pathogen. • able to distinguish b/w self and nonself, recognize and specifically react to large numbers of different microbes and pathogens, and remember the specific agents. • It involves two distinct but interconnected mechanisms: humoral and cell-mediated responses. Humoral provided by B lymphocyte and cell-mediated provided by T lymphocytes. Components of Immune Response The components of immune response are; LYMPHOID ORGANS Thymus, Spleen, Bone Marrow, Lymph Node NONSPECIFIC DEFENSES Complement, Acute Phase Response, phagocytosis CELL MEDIATED IMMUNITY T-Lymphocytes: Helper (Th1, Th2), Suppressor/ Cytotoxic, Naïve/Memory HUMORAL MEDIATED IMMUNITY B-lymphocytes Immunoglobulins (IgA, IgM, IgG, IgE & IgD) Cont… ANTIGEN Any substance that is able to cause an immune response in the body. Eg: include bacteria, chemicals, toxins, viruses and pollen. Cells in the body, as well as cancer cells, ha ve antigens that can cause an immune resp onse. ANTIGEN PRESENTING CELL (APC) Cells, such as macrophages, dendritic cells and B cells, that can process protein antigens into p eptides. These peptides can then be presented (along w ith major histo-compatibility complex) to T-cell receptors on the surface of the cell. Cont… ANTIBODY (IMMUNOGLOBULIN) (Ig) Special proteins created by white blood cells that can kill or weaken infection-causing organisms. Antibodies travel through the blood stream looking for specific pathogens. Body can create new antibodies in response to new pathogens or vaccines. BASOPHIL A basophil is a type of phagocytic immune cell that has granules. Inflammation causes basophi ls to release histamine during allergic reactions. Cont… BASOPHIL A type of phagocytic immune cell that has granules. Inflammation causes basophils to release histamine during allergic reactions. B-LYMPHOCYTE (B-Cell) B-lymphocyte is a type of WBC that develops in the bone marrow and makes antibodies. MEMORY B CELL B cells that are long lived and remember past antigen exposure. PLASMA B CELL Activated B cells that produce antibodies. Only one type of antibody is produced per plasma B cell. Cont… CYTOKINE A type of protein that impacts immune system by either ramping it up or slowing it down. Cytokines can occur naturally in the body or be produced in laboratory (Interferon-alpha2b). DENDRITIC CELL are antigen-presenting cells (APCs). Antigen is combined with major histocompatibility complex and presented on a dendritic cell to active T and B lymphocytes. EOSINOPHIL A type of immune cell (leukocyte). They help fight infection or cause inflammation. Cont… GRANULOCYTE including eosinophils, neutrophils & basophils, type of WBC that releases toxic materials, such as antimicrobial agents, enzymes, nitrogen oxides & other proteins, during an attack from a pathogen HUMAN LEUKOCYTE ANTIGENS Human version of the major histo-compatibility complex (MHC). The MHC complex is a family of 200+ genes categorized into three classes: I, II, III Class I genes make proteins that are located on the surface of almost all cells. Class II genes are located on surface of immune cells. Class III genes are also involved with immune system and inflammation. Cont… NATURAL KILLER (NK) CELL The primary effector cell of innate immunity; th e first responders of the immune system. They i nteract with signals from other cells (activating and inhibitory). T-LYMPHOCYTE ( T-CELL) Type of WBC that is involved with the immune system. T lymphocytes mature in the thymus & differentiate into cytotoxic, memory, helper and regulatory T cells. CAR T-cell therapy uses T cells obtained from a patient’s own blood to fight cancer. grown and modified in a lab to include special receptors (ch imeric antigen receptor) that can recognize and attack cancer cells Cont… CYTOTOXIC T-CELL Are primary effector cells of adaptive immunity. Activated cytotoxic T cells can migrate through blood vessel walls and non-lymphoid tissues. They can also travel across blood brain barrier. Cytotoxic T cells are activated by cytokines. They can attach to cancer cells and kill them. MEMORY T-CELL Derived from activated cytotoxic T cells, they are long-lived and antigen-experienced. One memory T cell can produce multiple cytotoxic T cells. After activated cytotoxic T cells attack the pathogen, the memory T cells hang around to mitigate any recurrence. Cont… HELPER T-CELL secrete cytokines that help B cells differentiate into plasma cells. These cells also help to activate cytotoxic T cells and macrophages. REGULATORY T-CELL Regulatory T cells (or Tregs) help to suppress the immune system. LYMPHOCYTE Lymphocytes are immune cells found in blood and lymph tissue. T and B lymphocytes are the two main types. Cont… MACROPHAGE Macrophages are large white blood cells that reside in tissues that specialize in engulfing & digesting cellular debris, pathogens and other foreign substances in the body. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) A group of genes that code for proteins on the cells of the immune system. Referred to as the human leukocyte antigen (HLA) system. MAST CELL Mast cells release histamine and help to get rid of allergens. Cont… MONOCYTE Large WBC that reside in the blood stream that specialize in engulfing and digesting cellular debris, pathogens and other foreign substances in the body. Monocytes become macrophages. MYELOID-DERIVED SUPPRESSOR CELLS When immature myeloid cells cannot differentiate into mature myeloid cells, due to conditions like cancer, expansion of myeloid-derived suppressor cells occurs, and the T-cell response can be suppressed. Cont… NEUTROPHIL A type of white blood cell, granulocyte, and phagocyte that aids in fighting infection. Neutrophils kill pathogens by ingesting them. PHAGOCYTES Phagocytes eat up pathogens by attaching to & wrapping around pathogen to engulf it. Once pathogen is trapped inside phagocyte, it is in a compartment called a phagosome. Phagosome will then merge with a lysosome or granule to form a phagolysosome, where pathogen is killed by toxic materials, such as antimicrobial agents, enzymes,nitrogen oxides or other proteins. Humoral Versus Cell Mediated Immunity Humoral immunity is mediated by B-lymphocyte activation and subsequent antibody production. It is the • primary defense against extracellular microbes & toxins. In contrast, cell-mediated immunity involves activation of specific T lymphocytes (T-helper and T-cytotoxic), which are responsible for the body’s defense against intracellular microbes such as viruses. Humoral immunity consists of protection provided by B-lymphocyte– derived plasma cells, which produce anti bodies that travel in blood & interact with circulating and cell surface antigens. While, cell-mediated immunity provides protection through cytotoxic T lymphocytes, which protect against virus-infected or cancer cells. Cell-mediated immunity In cell-mediated immunity, T cells respond directly to antigens (foreign substances, such as bacteria or toxins, that induce antibody formation). Response involves destruction of target cell such as virus-infected cells & cancer cell through secretion of lymphokines (lymph proteins). Example: rejection of transplanted organ& delayed immune responses that fight disease. Cell-mediated immunity 36% of WBCs are T cells Thought to originate from stem cells in the bone marrow; the thymus gland controls their maturity. In process, a large number of antigen-specific cells are produced. T cells can be killer, helper, or suppressor Killer cells bind to the surface of invading cell, disrupt the membrane, & destroy it by altering its internal environment. Helper cells stimulate B cells to mature into plasma cells, which begin to synthesize & secrete immunoglobulin (proteins; antibody activity). Suppressor cells reduce humoral response. Humoral immunity B cells act in a different way than T cells to recognize and destroy antigens. B cells are responsible for humoral or immunoglobulinmediated immunity. B cells originate in the bone marrow and mature into plasma cells that produce antibodies (immunoglobulin molecules that interact with a specific antigen). Antibodies destroy bacteria and viruses, thereby preventing them from entering host cells. T Cells attack the antigen directly B cells produce antibodies that incapcitate the antigen Antigen Processing & Presentation •Antigen processing and presentation is process by which protein antigen is ingested by antigen-presenting cell (APC), partially digested into peptide fragments and then displayed on the surface of APC associated with antigen-presenting molecule such as MHC class I or MHC class II, for recognition by certain lymphocytes such as T cells. •Antigens are often presented to T-cells & upon recognition T-cells become activated. Antigen Presentation and The Immune Response Activation of T helper cells CD4+ Activation of B cells “humoral immunity” TH2 CD4+ CD8+ Activation of Cytotoxic T-cells “cell-mediated immunity” TH1 Antigen Recognition •Antigen recognition by B cells involves direct binding of immunoglobulin to intact antigen & antibodies typically bind to surface of protein antigens, contacting amino acids that are discontinuous in the primary structure but are brought together in the folded protein. •T cell receptors on the surface of T cells recognize the antigenic peptides bound to MHC molecules. With appropriate co-sti mulation & cytokine production, the T cell is activated •Unless T cell activation occurs, adaptive immunity does not develop. TYPES OF ANTIGENS •ENDOGENOUS ANTIGENS Antigens that are generated within cells of body; •Proteins encoded by genes of viruses (foreign) •Abnormal or altered ‘host’ proteins -Encoded by mutant genes (e.g. mutated proteins produced by cancer cells) TYPES OF ANTIGENS EXOGNEOUS ANTIGENS Antigens that enter the body from the environment; Invading Pathogens -Bacteria, Viruses, and Parasites INFECTIONS/DISEASE Inhaled Antigens -Proteins on cat hairs -Dust ASTHMA ATTACK -Pollen Ingested Antigens -Shellfish proteins -Peanuts ALLERGIC RESPONSES Antigens Introduced Beneath Skin -Splinter -Injected vaccine IMMUNIZATION Role of Ag Presenting Cells • Processing of antigen is required for recognition of an antigen by T cells. • Most cells in the body can present antigen with Class I MHC molecules. – This includes the presentation of foreign antigen and self-antigens. – CD8+ cytotoxic T cells recognize antigen bound to Class I. • Professional antigen-presenting cells present antigen with Class II MHC molecules. – CD4+ helper T cells recognize antigen bound to Class II. Professional Ag-Presenting Cells • Dendritic cells are the most effective – Immature dendritic cells in peripheral tissues express low levels of Class II molecules. These cells take up and process antigen, then move to lymph nodes. – Mature dendritic cells in lymphoid tissues express high levels of Class II molecules. These cells are the primary presenters of antigen. – Constitutively express B7 and other costimulatory molecules – Present peptides, viral antigens, and allergens Continue • Macrophages – Must be activated by phagocytosis of bacteria a nd by cytokines to express Class II molecules – Must be activated to express costimulatory mole cules – Present particulate antigens: intracellular and ext racellular pathogens • B cells – Constitutively express class II MHC molecules – Must be activated by antigen binding to antibod y before they express costimulatory molecules – Present soluble antigens, toxins, viruses Antigen-Processing & Presentation Pathways • There are different antigen processing & presentation pathways for different MHC molecules. – Cytosolic Pathway: Presentation of antigen on Class I molecules requires intracellular protein synthesis of the endogenous antigen. – Endocytic Pathway: Presentation of antigen on Class II molecules requires the endocytic uptake of exogenous antigen. Antigen-Processing and Presentation Cytosolic Pathway • This pathway is used for presentation of endogenous antigens. • Endogenous proteins are constantly being synthesized and degraded. – Some of rapidly degraded proteins are defective ribosomal products (DRiPs) that are synthesized incorrectly. • Many are degraded to amino acids but some persist in the cytosol as peptides. • Some of these peptides are sampled by the immune system and presented on the cell surface bound to MHC Class I molecules. Endocytic Degradation Pathway • Exogenous antigens are processed through the endocytic degradation pathway. • Antigens are internalized into antigen presenting cells by phagocytosis or endocytosis or both. – Ms and dendritic cells internalize by phagocytosi s – B cells internalize by receptor-mediated endocyto sis • The internalized antigens are degraded in phagolys osomes or endosomes. • The antigenic peptides are associated with Class II MHC and expressed on the cell surface. IMMEDIATE HYPERSENSITIVITY •Type I, II & III hypersensitivity reactions are known as immediate hypersensitivity reactions because they occur within 24 hours of exposure to antigen or allergen •Immediate hypersensitivity reactions are predominantly mediated by IgE, IgM, an d IgG antibodies. DELAYED HYPERSENSITIVITY •Known as Cell-mediated hypersensitivity • State in which an individual reacts with allergic effects caused by the reaction of antigenspecific T-lymphocytes after exposure to a certain substance (allergen) after having been exposed previously to the same substance or chemical group. •appears 48-72 hours after antigen exposure •major mechanism of defense against various intracellular pathogens, including mycobacteria, fungi, & certain parasites, and it occu rs in transplant rejection & tumor immunity. Disorder of Immune Response • immune system underpins just about all of health • if anything goes wrong with it, then there can be serious problems for the body. • The things that can go wrong include: Immunodefciencies – immune system not working properly Autoimmune diseases – the immune system in a person is working too well and attacking cells of the person’s own body. Types of Immuno-Deficiency 1. Primary immunodeficiency occurs as resul t of genetic mutations, 2. secondary immunodeficiency has external cause, such as infection (HIV) or chemicals. • Immunodeficiency can range from very mild to life threatening & treatment consists of supportive care, antibiotics & other similar drugs, improvement of nutrition and general well- being. • some immunodeficiencies helped by injection of immunoglobulins (antibodies) to replace patient’s own. With secondary immunodefciencies, it may be possible to remove the cause of immunodefciency. For example, if immunodefciency is caused by drug (such as is given in chemotherapy for cancer , once drug has been discontinued, then immunodefciency resolves. Auto-immunity • caused by overreaction of immune system to an antigen • which can lead to immune system attacking body’s own cells. Examples of autoimmune diseases include: 1. Diabetes (immune system attacks cells in pancreas that secrete insulin). 2. Rheumatoid arthritis (cells of joints, such as fingers and knees, are attacked by immune system). 3. Allergy (caused by malfunctioning immune system). Allergy is a raised immune response to an allergen (peanuts, dust or pollen). AIDS (Acquired Immunodeficiency Syndrome) •Acquired immunodeficiency syndrome (AIDS) is a chronic, potentially life-threatening condition caused by the human immunodeficiency virus (HIV). By damaging immune system, HIV interferes with body's ability to fight infection and disease. •HIV is a sexually transmitted infection (STI). •spread by contact with infected blood •spread from mother to child during pregnancy, childbirth or breastfeeding. •no cure for HIV/AIDS, but medications can control infection & prevent progression of the disease Hypersensitivity • Hypersensitivity reactions are exaggerated or inappropriate immunologic responses occurring in response to an antigen or allergen. • Disorders caused by immune responses are collectively referred to hypersensitivity reactions. Hypersensitivity reactions are classified in to four types; Type I, Type II, Type III, & Type IV • They differ with respect to the specific components of immune response initiated, the onset of symptoms, and the eventual mechanism of injury Epidemiology of HIV Infection •HIV remains major global public health issue • an estimated 39.0 million people living with HIV at the end of 2022, •two thirds of whom (25.6 million) are in WHO African Region. •In 2022, 630 000 people died from HIVrelated causes & 1.3 million people acquired HIV. •There is no cure for HIV infection. However, with access to effective HIV prevention, diagnosis, treatment & care, enabling people living with HIV to lead long and healthy lives. Epidemiology of HIV Infection • global HIV strategies that are aligned with SDG target 3.3 of ending the HIV epidemic by 2030. •By 2025, 95% of all people living with HIV should have a diagnosis, 95% of those should be taking lifesaving antiretroviral treatment (ART) and 95% of PLHIV on treatment should achieve a suppressed viral load for the benefit of the person’s health and for reducing onward HIV transmission. Pathogenesis of HIV Infection •Once HIV enters body, the virus infects a large number of CD4+ T cells and replicates rapidly. •During this acute phase of infection, blood has a high number of HIV copies (viral load) that spread throughout the body, seeding in various organs, particularly the lymphoid organs such as thymus, spleen, & lymph nodes. •During this phase, the virus may integrate and hide in cell’s genetic material. Shielded from the immune system, the virus lies dormant for an extended period of time. Pathogenesis of HIV Infection •In acute phase of infection, up to 70% HIVinfected people suffer flu-like symptoms. •Two to 4 weeks after exposure to the virus, the immune system fights back with killer T cells (CD8+ T cells) and B-cell-produced antibodies. •At this point, HIV levels in the blood are dramatically reduced. •At the same time, CD4+ T cell counts rebound, and for some people the number rises to its original level. HIV disease progression –Acute infection Primary infection of cells in blood or mucosa (HIV directly infects T cells and microphages oris carried to those cells by dendritic cells) Viral replication in the regional lymph nodes leads to Exponential viral growth and widespread dissemination Development of anti-viral responses and symptoms of acute infection occur Decrease in plasma viral load and symptoms of acute infection resolve Clinical Manifestation of HIV Infection As virus continues to multiply & destroy immune cells, cells in body that help fight off germs may develop mild infections or chronic clinical manifestation such as: •Fever •Fatigue •Swollen lymph nodes — often one of first signs of HIV infection •Diarrhea •Weight loss •Oral yeast infection (thrush) •Shingles (herpes zoster) •Pneumonia TYPES OF HYPERSENSITIVITY 1. Type I, IgE-mediated disorders/ IgE-mediated allergic reactions) 2. Type II, antibody-mediated disorders/ tissue specific reactions 3. Type III, complement-mediated immune disorders/ immune complex reactions 4. Type IV, T cell–mediated disorders / cell-mediated reactions. Type I, Hypersensitivity IgE Mediated Hypersensitive reaction/ Anaphylactic Response • is mediated by IgE antibodies that are produced by immune system in response to environmental proteins (allergens) such as pollens, animal danders, or dust mites. • These antibodies (IgE) bind to mast cells and basophils, which contain histamine granules that are released in the reaction and cause inflammation. •Type I hypersensitivity reactions can be seen in bronchial asthma, allergic rhinitis, allergic dermatitis, food allergy, allergic conjunctivitis, and anaphylactic shock. Pathophysiology: Type I, Hypersensitivity •After a previous sensitization, IgE is produced & binds to Fc receptors on mast cells and basophils •On encountering allergen, it triggers cross-linking of mast-cell cytophilic IgE, causing activation of mast cells & their degranulation of mediators that cause an allergic reaction. • mediators that participate in this reaction include histamine and lipid mediators such as PAF, LTC4, & PGD2 that cause vascular leak, bronchoconstriction inflammation, and intestinal hypermotility. •Enzymes (e.g., tryptase causes tissue damage) and tumor necrosis factor (TNF) causes inflammation. E osinophils release cationic granule proteins, e.g., major basic protein (causes death of host cells and parasites) and enzymes (e.g., eosinophil peroxidase , which participates in tissue remodeling). Type II, hypersensitivity Ab Mediated Hypersensitive reaction/ Cytotoxic-Mediated Response •IgG and IgM mediate cytotoxic-mediated responses against cell surface and extracellular matrix proteins. •Immunoglobulins involved in this type of reaction damage cells by activating the complement system or by phagocytosis. •Type II hypersensitivity reactions can be seen in immune thrombocytopenia, autoimmune hemolytic anemia, and autoimmune neutropenia. Pathophysiology: Type II, Hypersensitivity •In type II hypersensitivity reactions, the antibodies against basement membranes produce nephritis in Goodpasture's syndro me. •Myasthenia gravis and Lambert-Eaton syndrome are caused by antibodies that reduce the amount of acetylcholine at motor endplates, and autoantibodies to an intercellular adhesion molecule causes pemphigus. Type III, hypersensitivity Ag-Ab Mediated Hypersensitive reaction/ Immunocomplex Reactions •mediated by IgM and IgG antibodies that react with soluble antigens forming antigen-antibody complexes. •Complement system becomes activated & releases chemotactic agents that attract neutrophils and cause inflammation and tissue damage as seen in vasculitis and glomerulonephritis. •Type III hypersensitivity reactions can classically be seen in serum sickness and A rthus reaction. Pathophysiology: Type III, Hypersensitivity •In type III hypersensitivity reactions,immune -complex deposition (ICD) causes autoimmune diseases, which are often a complication. •As disease progresses further accumulation of immune complexes occurs, and when the body becomes overloaded, the complexes are deposited in the tissues and cause inflammation as mononuclear phagocytes, erythrocytes, and complement system fail to remove immune complexes from the blood. Type IV, hypersensitivity Cell Mediated Hypersensitive reaction/ Cytotoxic-Mediated Response •IgG and IgM mediate cytotoxic-mediated responses against cell surface and extracellular matrix proteins. •Immunoglobulins involved in this type of reaction damage cells by activating the complement system or by phagocytosis. •Type II hypersensitivity reactions can be seen in immune thrombocytopenia, autoimmune hemolytic anemia, and autoimmune neutropenia. Pathophysiology: Type IV, Hypersensitivity • it is mediated by T cells that provoke an inflammatory reaction against exogenous or endogenous antigens. •In certain situations, other cells, such as monocytes, eosinophils, and neutrophils, can be involved. •After antigen exposure, initial local immune & inflammatory response occurs that attracts leukocytes. Antigen engulfed by macrophages and monocytes is presented to T cells, which then becomes sensitized and activated. These cells then release cytokines and chemokines, which can cause tissue damage and may result in illnesses.
