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Immunity and Inflammation:

Basic Concepts

The common periodontal diseases found in humans are gingivitis and periodontitis These are inflammatory responses in the periodontal tissues induced by microorganisms in dental plaque, which may lead to tissue destruction

Immune responses are categorized as:


Innate immune responses do not adapt with repeated exposure to the same pathogen
Phagocytic cells (eg. monocytes, macrophages, and neutrophils)

Specific adaptive immune response will increase after exposure to a pathogen


Lymphocytes (e.g., T-cells and B-cells) are important in the fundamental form of specific adaptive immunity referred to as the specific immune response

Inflammation is an observable alteration in tissues associated with changes in vascular permeability and dilation, often with the infiltration of leukocytes into affected tissues Causes erythema, edema, heat, pain, and loss of function "cardinal signs" of inflammation Progresses through three stages: immediate, acute, and chronic Leukocytes, the white blood cells, control all three stages of inflammation

Leukocytes originate in the bone marrow and exit from the blood by transendothelial migration under normal conditions

Among the most important resident leukocytes are mast cells, peripheral dendritic cells (DC), and monocyte derivatives such as dermal dendrocytes (histiocytes)

These resident leukocytes transmit information that initiates the processes of immediate inflammation Immediate inflammation is followed within minutes by a short-lived period (up to several hours) of acute inflammation that is characterized by an influx of neutrophils to the area after they exit the blood

If the problem is left untreated, acute inflammation gives way to a potentially unending period of chronic inflammation dominated by the migration of lymphocytes and macrophages to the local tissues The leukocytes recruited into tissues in acute and chronic inflammation are termed inflammatory leukocytes

CELLS OF IMMUNITY AND INFLAMMATION

Cells of the immune system that are important in inflammation and host defenses include: mast cells, dermal dendrocytes (histiocytes), peripheral dendritic cells, neutrophils, monocytes/macrophages, T:cells, B-cells, and NK-cells Other hematopoietic leukocytes (i.e., basophils, eosinophils, erythrocytes, and platelets) also participate in certain forms of inflammation or immune function

Cells possess receptors, which are molecules on the cell surfaces that enable the cell to interact with other molecules or cells Receptors reflect and dictate the function of cells The names given to receptors often related to function these common names, a systematic nomenclature known as the CD (cluster of differentiation) system has been developed

Mast cells
Important in immediate inflammation Possess receptors for complement components (C3a and C5a) as well as receptors for the Fc portion of the antibody molecules IgE and IgG (FcR and FcR, respectively)

The stimulation of these receptors can result in activation and secretion of vasoactive substances that increase vascular permeability and dilation, two important signs of anaphylaxis Anaphylaxis can be life threatening if it is widespread (systemic), but it is usually localized and is important in initiating inflammatory responses against local microbial invasion

Mast cells feature prominent cytoplasmic granules, termed lysosomes, which store inflammatory mediators such as histamine, eosinophil chemotactic factor,neutrophil chemotactic factor, and heparin Mast cells can synthesize, other inflammatory mediators, such as the slow-reacting substances of anaphylaxis (SRS-A), tumor necrosis factor- (TNF- ), and leukotriene C4

Dermal Dendrocytes
These cells are distributed near blood vessels and possess receptors for the component C3a Participate in immediate inflammation They express the major histocompatibility complex (MHC) Class II molecules

Peripheral Dendritic Cells


These cells are distributed near blood vessels and possess receptors for the component C3a Participate in immediate inflammation They express the major histocompatibility complex (MHC) Class II molecules

Neutrophils and Monocytes/Macrophages


Neutrophils and monocytes are closely related phagocytic leukocytes The difference between these two cells is that neutrophils differentiate almost completely within the bone marrow (14 days), monocytes exit the bone marrow after 2 days in a relatively immature state and may differentiate in the tissues

The same size (10m diameter) in the blood Neutrophils (also known as polyrmorphonuclear leukocytes or PMNs) are the predominant leukocyte in blood accounting for about 2/3 of all blood leukocytes (4000-8000 cells/mm3) They possess many lysosomes within their cytoplasm Because neutrophils do not need to differentiate substantially to function, they are suited for rapid responses

Neutrophils possess receptors for metabolites of the complement molecule C3, designated complement receptor 1, 3, and 4 (CRl, CR3, CR4); and C5 (CSaR) They also possess receptors for IgG antibody (FcR) These receptors enable neutrophils to participate in the inflammatory response and ingest foreign molecules and cells in the process of phagocytosis

Monocytes are referred to as macrophages when they leave the blood They complete their differentiation in the local tissues and may become greater than 22m diameter Macrophages differentiate and live in the local tissues, they are suited for communicating with lymphocytes and other surrounding cells

Macrophages live long enough to present antigen to T-cells Together, macrophages and lymphocytes orchestrate the chronic immune response Monocytes/macrophages possess CRl, CR3, CR4, C5aR receptors, several classes of Fc receptors (FcRI, FcRII, FcRIII), and molecules important in antigen presentation (MHC Class II receptor, CDl)

Lymphocytes
Three main types of lymphocytes are distinguished on the basis of their receptors for antigens: T- and B-lymphocytes and natural killer (NK) cells

T-Cells
T-cells recognize diverse antigens using a low affinity transmembranous complex, the T-cell antigen rceptor e Antigens are recognized by T-cells in association with either MHC Class I or Class II molecules on the surface of the antigen presenting cell

T-cells are subdivided based on whether they possess the coreceptors CD4 or CD8 CD4 coreceptor reversibly binds (scans for) MHC Class II molecules (HLA-DR, HLA-DP, HLA-DQ) that are found on dendritic cells, macrophages, and B-cells CD4+ T-cells initiate and help with immune responses by providing proliferative and differentiative signals

CD8 coreceptor scans for MHC Class I molecules, which are found on all cells CD8+ T-cells are predominantly cytotoxic T-cells involved in controlling intracellular antigens (e.g., certain bacteria, hyphal fungi, viruses)

B-Cells
B-cells help control extracellular antigens such as bacteria, fungal yeast, and virions B-cells recognize diverse antigen using the Bcell antigen receptor (BCR) which is a highaffinity antigen receptor The high-affinity interaction between BCR and antigen enables the B-cell to bind and ingest the antigen without antigen presentation

Natural Killer (NK) Cells


NK-cells recognize and kill certain tumor and virally infected cells NK-cells possess several classes of antigen receptors, including killer inhibitory receptors (KIR) and killer activated receptors (KAR)

COMPLEMENT

Complement (C) is an interacting network of about 30 membrane-associated cell receptors and soluble serum glycoproteins

Most soluble components are synthesized in the liver, but many also may be produced by macrophages (Cl, C2, C3, C4, C5, Factor B, CI-INA, Factor D, and Factor H)

The complement system is a central component of inflammation that enables endothelium and leukocytes to recognize and bind foreign substances for which they lack receptors Complement promotes inflammation by generating the following:

A vasoactive substance, termed kinin-like, C2a, which induces pain, increases vascular permeability and dilation Molecules, termed anaphylatoxins, C3a and C5a, which produce anaphylaxis by inducing mast cell secretion A chemotaxin, C5a, which attracts leukocytes and stimulates phagocyte secretion An opsonin, iC3b, covalently bound to molecular aggregates, particles, or cells, which enables phagocytes to ingest them

C3 is the most important component of complement It also is the predominant component, accounting for about one third of the total complement Internal thioester is the essential feature of C3, and it shares this feature with the related molecule, C4

Splitting of C3 forms C3a and C3b and exposes the internal thioester bond residing within the C3b fragment Two main pathways result in the splitting of C3, the alternative and the classical pathways The outcome of C3b generation is dictated by the presence or absence of the regulators of complement activation

Both the alternative pathway and classical pathway lead to inflammation and phagocytosis through an enzyme that is designated a bound C3 convertase The altemative pathway is initiated without provocation by a spontaneous hydrolysis of the internal thioester bond of C3 by water

The classical pathway is initiated in response to the presence of some irritant Irritants include antibody-antigen complexes, certain membranes, or suspicious polymers This pathway involves the activation of a serine protease which has attached to an irritant

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