IMMUNOLOGY Dr. Nadeem Ikram MBBS, DCP (Clinical pathology), FCPS (Immunology)

IMMUNOLOGY  Divided into two major categories  Normal individual has two levels of defense against foreign agents Innate, Natural or non specific Immunity Acquired, Specific or adaptive Immunity

Non specific or Innate Immunity  First line of defense  Response is antigen independent  No memory of an encounter with a foreign organism

Elements of non specific or innate immunity  Anatomic barrier  Physiologic barrier  Secretory molecules  Cellular components

ANATOMIC BARRIER  Skin  Mucous membrane  Intestinal movement  Oscillation of bronchopulmonary cilia  Hairs in ears and nose

PHYSIOLOGIC FACTORS  pH  temperature  oxygen tension  acid environment of stomach  commensal flora  cough reflex

SECRETARY MOLECULES  Acids in skin secretions  Bile acids in GIT  Lysozyme  Complement  Acute phase proteins  Interferon

Cellular component of the non specific Immune system Cellular components (non specific) Circulatory cells  Neutrophils (Polymorphonuclear leukocytes) %  Eosinophils 1-4%  Basophils <1%  Monocytes 2-8% Others  Dendritic cells  Natural Killer cells  Mast cells

Neutrophils  Most important cellular components in bacterial destruction  Relatively large  Most abundant WBC  Lobed nucleus

Eosinophils  Bilobed nuclei  Majority reside in connective tissues  Immune response against parasites and helminths  Increase in allergic reaction

Monocytes Circulate in the blood for 1 day. Enters the tissues to become macrophages (scavengers) Largest blood cell in the circulation Tissue macrophages: life span 2-4 months

Natural killer cells  Nonphagocytic  Directed against viral infection and malignancies  Resemble lymphocytes in morphology but larger

Phagocyte response to infection  Chemotaxis  Attachment  Phagocytosis  Intracellular killing

Properties of Specific or adaptive or acquired immunity Specificity Memory Diversity Tolerance

Types 1.Humoral immunity Formation of antibodies in response to an antigen & is mediated by B lymphocytes 2.Cell mediated immunity Mediated by T lymphocytes

Specific Immune Cells Lymphocytes 20-40% T cells B cells

10-15% of circulating lymphocytes Synthesize immunoglobulins

Antibodies Immunoglobulins are glycoproteins, produced by B lymphocytes plasma cells Structure 2 identical light polypeptide chains 2 identical heavy polypeptide chains

Functions of Antibodies IgG Cross placenta IgM Predominant antibody in primary immune response IgA Present in Secretions IgD Function remains unclear IgE It binds to basophils & tissue mast cells Involved in allergic reactions Immunity against parasites and helminthes

Antibody Response Primary response: Following primary antigenic challenge 1.Lag phase 2.Log phase 3.Plateau phase 4.Decline phase Secondary response: Secondary antigenic challenge 1.Short lag phase 2.Persist for longer period of time. 3.Attains a higher titer 4.Consist predominantly of IgG antibodies

Effector functions of Antibodies Neutralisation Opsonization Antibody dependent cell mediated cytotoxicity Complement activation

T cells %of circulating lymphocytes Mature in thymus and called T lymphocytes

T cell subsets T helper cell (CD4) T cytotoxic cell (CD8)

Antigen presenting cells Antigen presenting cells located in the epithelium and tissues, capture antigens, transport them to peripheral lymphoid tissues, and displays them to lymphocytes Langerhan’s cells Interdigitating dendritic cells  Macrophages B cells

Activation of T cells Activation of T cells occurs by antigen presenting cells

MHC class I and II receptors

MHC Class I and II : Activation and proliferation of T and B cells

Function of MHC Class I Present antigen to CD8 T cells

Function of MHC Class II Present antigen to CD4 helper T cells

Activation of T cells First signal: Formation of MHC:TCR:(CD4/CD8) complex Second signal: Costimulatory molecules

B cell activation Activation by T dependent antigens B cell presents antigen to T cell, and receives signal from T cells for division and differentiation Antigen is protein in nature

Hypersensitivity Exaggerated or inappropriate immunological reactions leading to host tissue damage Or Immune responses capable of causing tissue injury and disease

TYPES OF HYPERSENSITIVITY REACTIONS Based on immunological mechanism that mediates disease Type I or Immediate / anaphylactic / atopy Type II or Cytotoxic / antibody mediated Type III or immune complex disease Type IV or cell mediated/ delayed

Hypersensitivity Type I Rapidly developing immunological reaction occuring with in minutes after combination of an antigen with antibody bound to mast cells or basophils in individuals previously sensitized to the antigen

Mechanism Antigen (allergen) binds to IgE on the surface of mast cells/basophils with the consequent release of mediators Reaction time is 5-30 minutes from the time of exposure to the antigen

Type I hypersensitivity Localized reactions Skin Eyes Nasopharynx Bronchopulmonary tissue GIT Systemic reactions (anaphylaxis)

Hypersensitivity Type II Antibodies (IgM, and IgG) that react with antigens present on cell surface or in the extracellular matrix Antigen Endogenous : intrinsic to the cell membrane or matrix Exogenous: drug metabolite

Examples of Type II Hypersensitivity Reaction against blood cells & platelets  Transfusion reactions  Hemolytic disease of new born  Autoimmune hemolytic anemia  Antibodies against neutrophils  Antibodies against platelets Reaction against tissue antigens  Good pasture's syndrome  Pemphigus vulgaris  Myasthenia gravis  Graves disease  Acute Rheumatic fever  Pernicious anemia  Hyperacute graft rejection

IMMUNE COMPLEX MEDIATED INJURY (TYPE III) Inflammatory reaction triggered by a soluble antigen forming large insoluable immune complexes with IgG or IgM antibodies in the circulation

ETIOLOGY Exogenous Infectious agents Bacteria : streptococci Viruses : Hepatitis B, CMV Parasites : plasmodium sp. Fungi: Actinomycetes Drugs or chemicals Foreign serum Quinidine Heroin Endogenous Nuclear antigens Immunoglobulins Tumor antigens

MECHANISM Formation of antigen antibody complexes in the circulation Deposition of immune complexes in the blood vessels Tissue injury by Inflammatory reaction

Free Ag + Ab Larger immune complex Deposit in tissue or blood vessel wall Inflammation MECHANISM OF DAMAGE

EXAMPLES Localized Type Arthus reaction Systemic Type Serum sickness Systemic Lupus Erythematosus (SLE) Poststreptococcal glomerulonephritis Reactive arthritis Polyarteritis nodosa Hypersensitivity pneumonitis

HYPERSENSITIVITY TYPE IV Delayed type Hypersensitivity Cell mediated Hypersensitivity Immunopathological damage that occurs at about hours after exposure of a sensitized individual to an antigen The cell mediated hypersensitivity is initiated by specifically sensitized T lymphocytes

HYPERSENSITIVITY TYPE IV Examples of diseases Type I diabetes mellitus Multiple sclerosis Contact dermatitis Peripheral neuropathy Chronic graft rejection Tuberculosis Environmental antigens (contact sensitivity)