Organization of the Immune System Immunity Innate Immunity Specific Immunity Immune Response Regulation of Immune Response Autoimmunity

nity Hypersensitivity Endocrinological influences

Dr Noor Wijayahadi

Organization of The Immune System

Cells of the Immune System Non-specific Immunity Phagocytic cells mononuclear cells : monocytes, macrophages polymorphonuclear cells : neutrophils eosinophils

Mediator cells basophils, mast cells, platelets

Specific Immunity

Lymphocytes 2 important features i) the diversity of antigen specificity ii) phenotypic and functional heterogeneity
B cells : CD19, CD20, CD21 T helper cells (TH) : CD4 T cytotoxic cells (Tc) : CD8 Natural killer cells (NK)

Memory cells both B and T cells that have been previously stimulated with antigens

Tissues of the Immune System

Generative organs (primary lymphoid) Bone marrow precursors of all blood cells,including lymphocytes Myeloid : erythrocyte and platelet granulocyte (neutrophil, eosinophil, basophil, mast cell) monocyte (macrophage) Lymphoid : B-lymphocyte, T-lymphocyte, NK cell site of B cell maturation Thymus site of T cell maturation

Peripheral tissues (secondary lymphoid) sites of specific immune responses recognition and activation phases lymph nodes, spleen, mucosal lymphoid tissues (Peyers patches, tonsils), cutaneous immune system

Lymphocyte recirculation and homing

Tissue

Spleen

Lymph node

Thoracic duct

 High endothelial cells cuboidal cells found in a specialized region of postcapillary venules process of migration of lymphocytes between HEC to enter the node is dependent on interactions between cell surface adhesion molecules (selectins and intergrins) and their coligands

IMMUNITY
The Immune System is a multicomponent defence and surveillance system whose function is to recognize self from nonself and to defend the body against nonself => immunesurveillance

Functionally divided into Innate Immunity Acquired Immunity

INNATE IMMUNITY
First line of host defence against infection Non-specific Anatomical barriers epithelium: skin, respiratory and gastrointestinal tracts Physiological barriers cough reflex, sneezing, flushing of urine Phagocytosis and inflammatory response Chemical barriers interferons, transferin, complement

SPECIFIC IMMUNITY
Exquisitely specific for different microbes Stimulated by exposure to foreign microbes Enhances / amplifies the mechanisms of innate immunity Provides the best defence against persistent or recurrent microbial infections Adapts to respond in specialized ways to individual microbes Types of specific immunity humoral versus cellular (antibody mediated) (cell mediated) active versus passive

Immune Response
The first exposure to antigen is called a primary response. The immune system responds much more rapidly when the same antigen enters the body again (secondary response). This phenomenon is known as immunologic memory Phases of Immune Response Antigen recognition Lymphocyte activation Antigen elimination

Antigen Recognition & Processing

Antigen
MHC-II

TCR

B7 Macrophage

CD28 Lymphocyte T

 Macrophages respond by increasing costimulator and secreting cytokines Antigen proteolytically degraded by APC and peptides derived presented on cell surface of APC bound to MHC proteins T cells only recognize antigen in the form of peptide-MHC complexes through T cell reseptor (TCR) CD4 : peptide-MHC class II complex (antigens derived from extracellular microbes) CD8 : peptide-MHC class I complex (antigens derived from intracellular microbes, viruses, tumours, transplantation tissues)

 B cell uses surface Ig (sIg) to recognize antigen which is internalized and presented to T cell as peptide-MHC class II complex - T-dependent antigen Lipopolysaccharide activates irrespective of sIg (T-independent antigen) Repeating antigen (e.g. complex sugars) cross-links sIg and activates B cell - (T-independent antigen)

Complement breakdown products bind to specific receptors on B cells and function as second signals for B cell activation

Lymphocyte Activation
Il-12, TNF- IFN- NK cell

Macrophage

IL-12

IFN-

IFN-
TH1

TH2

Cross-regulation
Il-4, IL-10 IL-4 IL-5 IL-6 IL-10 IL-13

IL-2 IFN- TNF-

Promotes cellular immunity

Promotes humoral immunity

Lymphocyte Activation
T and B cells undergo proliferation and clonal expansion T helper (TH1, TH2), T cytotoxic (TC), T suppressor (TS), T memory antibody producing B cells (plasma cells), B memory

TH cells develop into effector cells that function by secreting cytokines

Different cytokines act on B cells, T cells and macrophages

Antigen Elimination
Cellular Immunity
MHC-II

Microbe (bacteria) surviving in phagocyte

CD4 recognizes exogenous antigen

MHC-I

Activation of microbicidal functions of phagocyte

Microbe (virus) infecting non-phagocytic cell

CD8 recognizes endogenous antigen

Lysis of infected cell

Antigen Elimination
The elimination of antigens in the effector phase of specific immune responses occurs by the cooperative actions of differentiated lymphocytes and defence mechanisms of innate immunity In cell-mediated immunity, activated T lymphocytes secrete cytokines, which enhance the functions of phagocytes and other inflammatory leukocytes However, cytotoxic T cells do not require other cooperating mechanisms to eradicate microbes

Humoral Immunity
Y Y Y Y

Y Y
Extracellular microbes and toxins Antibodies

Y Y
Complement activation

Opsonization

YYYY

Y
Macrophage activation

Lysis of target cell Neutralization Opsonization

Killer (K) Cell

Target cell

granzymes

Antibody
Perforine

Antigen on surface of infected cell

Lysis of target cell

Perforine lysis by osmosis Granzyme - apoptosis

NK cell

 In humoral immunity,
antibodies bind to foreign antigens and enhance phagocytosis by blood neutrophils and mononuclear phagocytes antibodies also activate the complement system, which participates in the lysis and phagocytosis of microbes antibodies bind to foreign antigens and inhibits binding to receptors on the target cells antibodies also participate in lysis of target cells by NK cells

Regulation of Immune Response

Biologic significance of shutting off immune response

Homeostasis returning the immune system to rest after it responded to foreign antigens Self-tolerance preventing immune reactions to self antigens

Immunoregulation
Antigen Feedback inhibition IL-1 IL-1 Stimulation

Suppresor T cell

Macrophage

Helper T cell
IL-2

Y Y Y Y Y Y

B cell

Idiotype network interactions

Mechanisms
Antigen elimination plasma cells are short-lived Idiotypic network Suppressor T lymphocytes cytokines : IL-10 and IFN inhibit lymphocyte proliferation and effector functions Activation-induced cell death IL-2 triggers co-expression of death receptor (Fas) and its ligand --> apoptosis CTL-4 expression receptor for B7 molecules on APCs --> shuts off T cell responses

Autoimmunity

Failure or breakdown of self-tolerance Immunological Tolerance (unresponsiveness) specific unresponsiveness to an antigen induced by exposure to that antigen Immunopathogenesis antibodies (autoantibodies, immune-complexes) T cells (delayed-type hypersensitivity, cytolysis)

 Autoimmune diseases broad spectrum organ-specific (localized) systemic (generalized) Multiple contributing factors Immunologic - failure of activation-induced T cell death - antigen receptor: independent stimulation of autoreactive lymphocyte - cross-reactions between foreign and self antigens Genetic MHC genes linked to HLA haplotype A1 B8 DR3 : Addisons disease, thyroiditis DR3 + DR4 : IDDM

Environmental Hormones male : female (1 : 2) peak age of onset within reproductive years evidence of estrogens as triggering factors estrogens can stimulate certain types of immune response pituitary hormone prolactin has immunostimulatory actions particularly on T cells

Infections - cross-reactions between microbial and self antigens - polyclonal lymphocyte activation tissue damage; release of sequestered self antigens

Mechanisms of tissue damage

Type II hypersensitivity Graves disease Insulin receptor antibody syndrome Type IV hypersensitivity Hashimotos thyroiditis IDDM

Hypersensitivity
Hypersensitivity is the term used to describe exaggerated or inappropriate immune responses that result in tissue damage Recognition of antigen by the immune system can cause incidental tissue damage as well as the intended destruction of the antigen Gell and Coombs classification 4 types of hypersensitivity reactions (type I-IV) Reaction usually not confined to a single type

Hypersensitivity Type I
Main effector cells: mast cells and basophils They display Fc receptors for IgE molecules and possess granules (histamine, heparin,serotonin, chemotactic factors) Second exposure to homologous allergen crosslinks cell surface IgE molecules, initiates degranulation, and releases preformed and newly synthesized mediators (prostaglandins, leukotrines, platelet-activating factor) late-phase response : hyperresponsiveness not responsive to antihistamines

 T cells,eosinophils and neutrophils are involved in the pathology of clinical allergies such as asthma The tendency to allergic reactions (atopy) has both inherited and environmental components

Hypersensitivity Type II
Antibody-dependent cytotoxicity Antibody targets cell surface antigens

Target cell surface antigens may be altered self or exogenous cells (hyperacute graft rejection)
generally involves harmful immune responses to surface antigens of red blood cells, platelets, or granulocytes

Hypersensitivity Type III

Immune complex-mediated soluble immune complexes may be deposited in tissues or vessels (SLE) or form in tissues (farmers lung)

Hypersensitivity Type IV
Cell-mediated the central cells are the CD4 T lymphocytes and the macrophages Resulting from T lymphocyte reactions is usually delayed in onset (peaks at 48-72 hours) Granulomata are characteristic Contact dermatitis is a typical clinical example

Endocrinological influences of immune functions

Interactions between immune and nervous systems modulate host susceptibility and resistance to inflammatory disease Neuroendocrine regulation of inflammatory and immune responses occurs at multiple levels systemically: through anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation regionally: through production of glucocorticoids within and sympathetic innervations of immune organs eg. thymus locally: at sites of inflammation

 Glucocorticoids suppress cell adhesion, margination and migration, macrophage activation, antigen presentation, T cell receptor expression, T lymphocyte activation, proliferation, differentiation and mature cell function, including cytotoxicity, and B cell function including antibody production Physiological levels of glucocorticoids are immunomodulatory rather than immunosuppressive shift cytokine production from TH1 to TH2 pattern Other hormones regulate immune responses estrogen, prolactin, thyroid hormone, growth hormone, insulin-like growth factor-I, androgens