محاضرة مناعت مدرس المادة :ا.م. هدى عبدالهادي علي النصراوي Immunity to Infectious Diseases

محاضرة مناعت مدرس المادة :ا.م. هدى عبدالهادي علي النصراوي Immunity to Infectious Diseases Immunity to infection depends on a combination of innate mechanisms (phagocytosis, complement, etc.) and antigen specific adaptive responses (antibody, effector T lymphocytes).the immune system regulates which specific responses predominate (humeral and cell-mediated) based on the body compartment infected (intracellular or extracellular) and on cytokine signals present at initial antigen contact (Th1 and Th2 responses). Disease-causing microbes have virulence mechanisms that resist or evade innate and/or specific immune effector functions. The immune system is specialized to generate different effector mechanisms for different types of microbes Extracellular microbes: antibodies, phagocytes; TH17, (TH1) Intracellular microbes: phagocytes + TH1; CTLs Helminthic parasites: IgE, eosinophils; TH2 Principal mechanisms of defense against microbes Immunity against bacteria Most bacterial infections, e.g. a boil, are localized and dealt with by cells residing in the affected tissue (e.g. Macrophages) and those recruited by the consequent

inflammatory response. In bacteremia, the response is correspondingly greater and the inflammatory response more severe. The complement proteins and humeral immune response are the key players Steps of Bacterial Infection 1. Attachment of bacterium to host tissue (Persistence and growth called colonization) 2. Invasion into deeper host tissues and production of toxins (Results in host cell and tissue injury) 3. Inflammation at site of invasion Initiated by:- A- Antibody binding to bacterium B- Complement activation at bacterial surface C- Wound healing mechanisms All can activate complement pathways that alters vascular permeability and activates local macrophage (M!) and neutrophils (PMNs) Attachment of bacterium to host tissue Invasion into deeper host tissues and production of toxins

Inflammation at site of invasion Immune System Function and Resistance to Bacterial Infection Immunity to extracellular and intracellular bacteria is dependent on different effector immune cells. The following example illustrates in a simplified outline the sequence of events leading to an immune response against bacteria. A-Innate immune strategies 1-The high-speed innate response may be all that is required to destroy a few infecting bacteria (e.g. from a splinter). 2-Lysozyme is a natural antibiotic. It acts on peptidoglycan in the bacterial cell wall causing lysis. 3-Complement proteins may lyse bacteria directly with membrane attack complexes or facilitate phagocytosis by opsonizing the cell. 4-Macrophages and other phagocytic cells eat bacterial cells either directly or aided by opsonization with complement or specific Ab. Once inside the cell they are destroyed by toxic enzymes. B-Adaptive immune responses to extracellular bacteria 1-Macrophages can present bacterial protein components on MHC class II activating specific T helper cells, these produce cytokines recruiting and activating other cells.

2-Specific B cells recognize Ag and with T-cell help activate and proliferate. The Ab produced may be to structural components on the surface (helping complement and phagocytosis), or may neutralize toxins produced by the bacteria (e.g. tetanus). Endotoxins are constituents of the cell wall (e.g. LPS); exotoxins are specifically secreted products Immunity to extracellular bacteria by antibodies: Gram negative bacteria 1-Antibodies and complement result in opsonization via Fc Receptors (FcR) or Complement Receptors (CR) on Macrophage and PMN 2- Antibody can activate classical complement pathway resulting membrane attack complex (MAC) and opsonization via CR 3- Antibodies can also trigger antibodydependent cell mediated cytotoxicity (ADCC) by PMN with Fc R and CR release proteases, nucleases, lipases, and ROIs Immunity to extracellular bacteria by antibodies: Gram positive bacteria 1-Antibodies and complement result in opsonization via Fc Receptors (FcR) or Complement Receptors (CR) on Macrophage and PMN Antibody cannot activate classical complement pathway resulting membrane attack complex (MAC) because of the thick cell wall, but can do opsonization via CR 2- Antibodies can also trigger antibodydependent cell mediated cytotoxicity (ADCC) by PMN with Fc R and CR release proteases, nucleases, lipases, and ROIs

Immunity to extracellular bacteria by antibodies C-Immunity to intracellular bacteria by cell mediated immunity (CMI) 1- Bacterial antigens present in the cytoplasm of infected host cell Processed via endogenous pathway and presented to CD8+ T cells (Cytotoxic T lymphocytes or CTLs) on MHC class I 2- Bacterial antigens present in the endosomes of infected host cell Processed via the exogenous pathway and presented to CD4+ helper T cells (TH) on MHC class II 3- Bacterial antigens present on the surface of the infected host cell can be bound by antibodies and targeted for killing by NK cells using ADCC and via proteases and ROI 4- Some TH cells (TH1) can initiate a DTH response Activates Macrophages and kill bacteria and host cell via proteases and ROI

Mechanisms of Immunity to intracellular bacteria by CMI Immunity against viruses A-Innate immunity plays a key role in resistance to viral infection Body surface Early non-specific or innate immune Interferons (IFN) are anitviral factors expressed by many cells when virally infected Natural Killer (NK) cells recognize virally infected cells and kill them via cytotoxicity Complement can opsonize viral particles for phagocytosis by M!

Interferon Interferons are proteins produced by cells infected with viruses, or exposed to certain other agents, which protect other cells against virus infection or decrease drastically the virus yield from such cells. Interferon itself is not directly the anti-viral agent, but it is the inducer of one or many anti-viral mechanisms. Anti-tumor and regulation of immunity Natural Killer (NK) cells The virally induced MHC class I down regulation triggers NK cells to kill the infected cells B-Adaptive (specific) immune response to viral infection Cytotoxic T lymphocytes (CTLs) Helper T (Th) cells Antiviral antibodies Recognize infected cells coated with antiviral antibodies using Fc receptors (FcR) and kill them through antibody dependent cell mediated cytotoxicity (ADCC) CTL recognize foreign viral peptides presented by MHC class I on the surface of infected cells. They are activated if they experience a co-stimulatory signal from a Th cell and proliferate.these activated CTLs can then trigger cell death on future encounters with their specific Ag MHC complex. Certain viruses cause a reduction in surface expression of MHC I in cells they have infected as a means of avoiding CTLs. NK cells become suspicious of cells with absent MHC I and are capable of killing these cells early in infection. Antibodies may bind viral surface antigens required for cell entry, thereby neutralizing the virus

Immunity against fungal infections The immune mechanisms of defense against fungal infections are numerous, and range from protective mechanisms that were present early in evolution (innate immunity) to sophisticated adaptive mechanisms that are induced specifically during infection and disease (adaptive immunity). Although fungal infections are usually eliminated by cell-mediated immunity alone, some require more than this. For example, whilst chronic mucocandidiasis may be cured by effective cell mediated immunity, recovery from systemic infection with Candida spp. requires the activity of granulocytes, cytokines from NK cells and others, complement and possibly humoral immunity. Thus, control of certain fungal infections requires the combined activity of the innate and specific immune responses. Innate immune responses to Fungi 1. Physical barriers: skin and mucosa 2. Chemical factors in serum and skin secretions 3. Phagocytic:-Neutrophils (PMNs) are most important phagocyte. Neutrophils important phagocytic cells. Recurrent or severe fungal infections may be seen in those with defective neutrophil responses. They are a key part of first-line defense in organs such as the lung Adaptive immune response to fungal infection includes: Antibody and complement responses these opsonize fungal cells and facilitate phagocytosis (e.g. Cryptococcus neoformans possesses an antiphagocytic capsule and can resist phagocytosis unless opsonized by antibody or complement). Antibody responses may also contribute to pathology (e.g. the hypersensitivity seen as part of infection with Aspergillus spp.)

T-cells severe infections of the skin and mucous membranes, as well as the lung and elsewhere are common in those with T-cell deficiencies. The response to chronic infection may lead to the development of granulomas. Immunity against parasites Parasites are generally complex organisms which invade through mucosal surfaces or the skin. Parasites have sophisticated mechanisms for evading the immune response and the most effective strategy is to prevent infection in the first place. The generation of IgE is dependent on the Th2 cytokine IL4. IL5 also secreted by Th2 cells recruits eosinophils which can kill parasites by exocytosing a cytotoxic protein, cationic basic protein. Th2 responses are maintained at mucosal sites by the following mechanism. IL4 reinforces Th2 responses by inhibiting Th1 cell development. Eosinophils and immunoglobulin E (IgE) production are important players in the immune response to infection with worms, but as a result hypersensitivity reactions in the skin and lung may occur. Eosinophilia results in part from mast cell and T-cell factors. Eosinophils phagocytize the antigen antibody complexes that circulate in enormous quantities in worm infection, and modulate hypersensitivity. They may also kill certain worms. IgE production is stimulated by the presence of worms, and the resulting inflammatory response is thought to reduce worm attachment and gut entry. Chronic infection with certain flukes (e.g. schistosomes) can lead to fibrosis of the liver or bladder as a result of a T-cell-mediated reaction to their trapped eggs Protozoa owe their success as pathogens to a combination of strategies aimed at avoiding the full force of the immune response. These include: Adopting an intracellular habitat (e.g. toxoplasmosis) rapid antigenic variation (e.g. African trypanosomes use a gene-switching mechanism to repeatedly replace their outer coat as fast as antibodies are raised against it) Immunosuppression (e.g. Toxoplasma suppresses T-cell function to facilitate its intracellular survival), and the generation of non-specific polyclonal B-cell responses which serve to inhibit the generation of effective specific immunity and may precipitate autoimmunity.