• Organization of the Immune System• Immunity Innate Immunity Specific Immunity• Immune Response• Regulation of Immune Response• Autoimmunity• 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 (Peyer’s patches, tonsils), cutaneous immune system

Lymphocyte recirculation and homing

Tissue

Spleen Lymph node

Thoracicduct

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

AntigenMHC-II

Macrophage

TCR

Lymphocyte T

B7CD28

• 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

Macrophage

NK cell

TH2TH1

IFN-

IL-1 IL-13

IL-12IFN-

IFN-

Il-12, TNF-

IFN-

Il-4, IL-10

Cross-regulation

Promotes cellular immunity Promotes humoral immunity

IL-4IL-5IL-6IL-10IL-13

IL-2 IFN-TNF-

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

Microbe (bacteria) surviving in phagocyte

MHC-II

CD4 recognizes exogenous antigen

Activation of microbicidal functions of phagocyte

MHC-I

CD8 recognizes endogenous antigen Lysis of infected cell

Microbe (virus) infecting non-phagocytic 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 YY Y

Y Y

Y

Extracellular microbes and toxins Antibodies Complement activation

Y Y Y Y

NeutralizationOpsonization

Opsonization

Macrophage activation

Lysis of target cell

Killer (K) Cell

Y

NK cell

Target cell

Antigen on surface of infected cell Antibody

Perforine

Lysis of target cellgranzymes

Perforine – lysis by osmosis

Granzyme - apoptosis

• 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

Y Y Y Y Y Y

Antigen

Macrophage IL-1

Suppresor T cell

IL-2

IL-1

Helper T cell

Suppression

Help

Stimulation

B cell

Feedbackinhibition

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 : Addison’s 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 Grave’s disease Insulin receptor antibody syndrome

Type IV hypersensitivity Hashimoto’s 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 cross-links 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 (farmer’s 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