2) Diseases of the Immune System 1, 2 and 3 (1)-1-20.pdf

Diseases of the Immune System Karoll John Bretaña MD The immune system is vital for survival because it protects us from infectious pathogens that abound in the environment and from the development of cancer. Predictably, immune deficiencies render individuals easy prey to infections and increase t...

Diseases of the Immune System Karoll John Bretaña MD The immune system is vital for survival because it protects us from infectious pathogens that abound in the environment and from the development of cancer. Predictably, immune deficiencies render individuals easy prey to infections and increase the incidence of certain cancers. But the immune system is itself capable of causing tissue injury and disease. Examples of disorders caused by immune responses include reactions to environmental substances that cause allergies and reactions against an individual's own tissues and cells (autoimmunity). This chapter is devoted to diseases caused by too little or too much immunologic reactivity. We also consider amyloidosis, a disease in which an abnormal protein, derived in many cases from immunoglobulins, is deposited in tissues. First, we review some of the important features of normal immune responses, to provide a foundation for understanding the abnormalities that give rise to immunologic diseases.our question here Statement of the problem: That’s a lot to memorize !!! Project Overview Include a brief overview or summary of your project Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances Pathogen-associated molecular patterns (THE microbial Structures) Cells that participate in innate immunity are capable of recognizing certain components that are shared among related microbes and that are often essential for infectivity (and thus cannot be mutated to allow the microbes to evade the defense mechanisms) Damage-associated molecular patterns Leukocytes also recognize molecules released by injured and necrotic cells Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances Pattern recognition receptors Collectively, the cellular receptors that recognize these molecules located in all cellular compartments where microbes may be present: plasma membrane receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm o Toll-like Receptors (TLRs) - plasma membrane and endosomal vesicles NOD-like Receptors (NLRs) -cytosolic receptors and also recognizes wide variety of substances FIGURE 6.2 Cellular receptors for microbes and products of cell injury Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. Major classes of innate immune receptors are TLRs, NOD-like receptors (NLRs) in the cytosol, C-type lectin receptors (CLRs), RIG-like receptors (RLRs) for viral nucleic acids, and cytosolic receptors for DNA (not shown). RIG, retinoic acid-inducible gene FIGURE 6.3 The inflammasome The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin 1 The inflammasome consists of a sensor protein (an example is the leucine-rich protein NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to an active form. ATP, Adenosine triphosphate; IL, interleukin; TLR, Toll-like receptor.  C-type lectin receptors (CLRs) Still receptors for expressed on the plasma membrane of macrophages and DCs detect fungal recognition glycans and elicit inflammatory reactions to fungi. RIG-like receptors (RLRs) named after the founding member RIG-I (retinoic acid-inducible gene-I) located in the cytosol of most cell types and detect nucleic acids of viruses that replicate in the cytoplasm of infected cells. stimulate the production of antiviral cytokines. Cytosolic receptors for microbial DNA, often derived from viruses in the cell, activate a pathway called STING (for stimulator of interferon genes), which leads to the production of the antiviral cytokine interferon-α. Excessive activation of the STING pathway causes systemic inflammatory disorders collectively called interferonopathies. Plasma membrane G protein– coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N-formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N-formylmethionine, this receptor enables neutrophils to detect bacterial proteins and move toward their source (chemotaxis). Mannose receptors recognize microbial sugars (which often contain terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes. Fungal or microbial NK cells Virus, Tumors = kill Class 1 MHC IL-12, IL-2 and IL-15 FIGURE 6.4 Activating and inhibitory receptors of natural killer (NK) cells (A) Healthy cells express self class I major histocompatibility complex (MHC) molecules, which are recognized by inhibitory receptors, thus ensuring that NK cells do not attack normal cells. Note that healthy cells may express ligands for activating receptors (not shown) or may not express such ligands (as shown), but they do not activate NK cells because they engage the inhibitory receptors. (B) (B) In infected and stressed cells, class I MHC is reduced so that the inhibitory receptors are not engaged, and ligands for activating receptors are expressed. The result is that NK cells are activated and the infected cells are killed. Adaptive Immunity FIGURE 6.5 The principal classes of lymphocytes and their functions B and T lymphocytes are the cells of adaptive immunity. Several other classes of lymphocytes have been identified, including NK-T cells and so-called innate lymphoid cells (ILCs); the functions of these cells are not as well established as those of B and T lymphocytes. T-lymphocytes - Thymus 3 types of T lymphocytes: Helper Cytotoxic (CTLs) Regulatory Bone Marrow DCs: APC Plasma cells : Ig production Memory cells 1. Thymus and BM 2. Lymph nodes, spleen and cutaneous lymphoid tissues Located where high chances of microbes can be encountered FIGURE 6.8 Morphology of a lymph node. (A) The histology of a lymph node, with an outer cortex containing follicles and an inner medulla. (B) The segregation of B cells and T cells in different regions of the lymph node, illustrated schematically. (C) The location of B cells (stained green, using the immunofluorescence technique) and T cells (stained red) in a lymph node. (Courtesy Drs. Kathryn Pape and Jennifer Walter, University of Minnesota School of Medicine, Minneapolis, Minn.) Major Histocompatibility Complex Molecules: the Peptide Display System of Adaptive Immunity The function of MHC molecules is to display peptide fragments of protein antigens for recognition by antigen-specific T cells. Because MHC molecules are fundamental to antigen recognition by T cells and are linked to many autoimmune diseases, it is important to briefly review their structure and function. MHC molecules were discovered as products of genes that evoke rejection of transplanted organs, and their name derives from their role in determining tissue compatibility between individuals. In humans, the MHC molecules are called human leukocyte antigens (HLA) because they were initially detected on leukocytes. The genes encoding HLA molecules are clustered on a small segment of chromosome 6. The HLA system is highly polymorphic; there are thousands of distinct MHC gene alleles in humans, and as a result each individual's HLA alleles differ from those inherited by most other individuals in the population. This, as we see subsequently, constitutes a formidable barrier in organ transplantation. FIGURE 6.9 The human leukocyte antigen (HLA) complex and the structure of HLA molecules (A) The location of genes in the HLA complex. The relative locations, sizes, and distances between genes are not to scale. Genes that encode several proteins involved in antigen processing (the TAP transporter, components of the proteasome, and HLA- DM) are located in the class II region (not shown). (B) Schematic diagrams and crystal structures of class I and class II HLA molecules. (Crystal structures are courtesy Dr. P. Bjorkman, California Institute of Technology, Pasadena, Calif.)