Unit 4 - The Immune Response

Briefly characterize nonspecific defense and innate mechanisms and how they differ from the specific immune response or adaptive immunity

• Cells sloughed from skin and mucous membranes routinely to remove foreign organisms

• Slightly acidic pH which prevents growth of some organisms

• Mucus secreted by digestive, urogenital and respiratory tracts = protective coating

• Cilia = move foreign particles out of the respiratory tract

• Cough mechanism = expel material (foreign particles) forcefully

• Lysozomes (tears), acid (stomach) and digestible enzymes also help

• Inflammation = nonspecific defense mechanism

  • neutrophils, macrophages, phagocytes = non-specific phagocytosis

• Macrophages = important in both immune response

• Major components = pattern recognition receptors that detect extracellular pathogens that display pathogen-associated molecular patterns

  • structural motifs that initiate immune responses

• Release damage-associated molecular patterns

  • motifs released by dying or damaged cells

The ADAPTIVE response is specific

• Memory = antigen is remembered and recognized

• Amplification = Enhanced secondary response on second exposure to antigen

Antigen = molecules that evoke an antibody response

• large molecules (protein or polysaccharide)

• Haptens = become antigenic if they complex with larger carrier molecules

Foreign agent = bacteria, viruses, protozoa and funghi

• binding of hapten/neoplastic transformation ( becoming cancerous) can show up as foreign bodies

Immunogen = molecules that elicit an immune response

Self-tolerance = natural tolerance or lack of response to one's own antigens

• clonal deletion = during embryonic development lymphocytes go through a selection procedure in the thymus (those reacting to self-tolerance molecules are deleted

Describe the origin and generation of both B (humeral immunity) and T lymphocytes (cell-mediated immunity), their functions and the different classes of T lymphocytes

When an antigen enters the body it is

1. Processed by antigen-presenting cells such as dendrites

2. Presented to lymphocytes (major effector cells of immune system)

3. Lymphocytes then proliferate and transform

T CELLS = Cell-mediated immunity

• transform into effector (Killer T cell) which destroy antigen-bearing cells

• Lymphokines produced and influence interaction between cells

• Helper and suppressor cells enhance and suppress the immune response

• Characterized by T-cell receptor complex on the surface

  • interact with specific fragments of antigens that have been

    • digested through phagocytosis and present on surface

    • expressed abnormally (viral and tumor cells)

• After interaction clonal expansion occurs

  1. CD4 (60% mature T cells)

     • helper T cells which secrete cytokines

     • TH1-lymphocytes respond to activation through release of Interferon-Gamma

       • activates macrophages and B-cells

         • secrete antibody isotopes that mediate phagocytosis + activate complement

     • TH2-lymphocytes release IL-4

       • stimulates B cells to differentiate to IgE secreting plasma cells

       • IL-5 and IL-13 also released

         • activates mast cells and eosinophils

         • Produces a reaction resembling Type I hypersensitivity response

  2. CD8 (30%)

     • cytotoxic = directly kill virus-infected cells/tumour cells

     • Lesser role in secretion of cytokines

Role of Activated T cells

1. Cell-mediated immunity

   • Cytotoxicity = direct killing of cells which is important in CD8 + T-cells

   • Kill any cell with a recognizable surface antigen (virus + transplanted + tumor)

2. Helper roles (regulation of B and T cell activity

   • produce cytokines (protein mediator) which influence functions of macrophages and lymphocytes

   • Help to synthesize B cells

   • Delayed hypersensitivity

B CELLS = Humoral Immunity

• humoral immunity = transformation of B cells into antibody-producing plasma cells (antibodies = immunoglobulins)

• Characterized by antibody-receptor complex on cell surface (interaction causes proliferation) and clonal expansion

• Antibody/Antigen interaction causes clonal expansion (B-cell proliferation)

  1. Plasma Cells = produce and secrete antibody that is specific for the antigen that originally triggered their differentiation

     • off-center nucleus + cartwheel chromatin pattern + abundant basophilic cytoplasm + obvious perinuclear clearing

     • IgG, IgM, IgA, IgE and IgD

  2. Memory cells = smaller population but persist longer

     • provide B-cells that react to antigens and invoke a rapid immune response (MEMORY B CELLS)

Natural Killer Cell = INNATE LYMPHOCYTE

• what are 3 features of NK cells?

Antigen - Presenting cells

• Macrophages = derived from blood monocytes

• Found in all tissues, concentrated in lymphoid tissues

• Macrophages play a key role in early immune response

• ANTIGEN PROCESSING ROLE

  • phagocytosis and internalization of Ag by macrophage

  • Ag is expressed a the macrophage surface with MHC molecules

Describe antibody production by B cells and the immunoglobulin classes

After antigen recognition, activation, and presentation to the B-cell the antibody, B cells proliferate and differentiate

• antibodies are then secreted from plasma cells and bind to and neutralize microbes

Immunoglobulins = a family of serum proteins (antibodies)

Immunoglobulin structure

• heavy and light chains which each have variable and invariable sequences

  • Constant part is the same in all members of similar Ig class (white)

  • Variable = variable in amino acid sequences and gives antigen specificity

    

ANTIBODY PRODUCTION

• Lymphocytes are derived from steel cells in bone marrow

  • those which migrate and develop further in the thymus = T lymphocytes

  • those that develop independently from the thymus (they develop in the bursa of Fabricius in birds or BONE MARROW) = B cell

• From bone marrow, they travel to peripheral lymphoid tissues (lymph nodes, spleen, tonsils, gut, and mucosal)

Development of Antibodies

• newborns rely on passively acquired IgG through the placenta in utero

• In the first few weeks of life, lymphoid tissue develop and immunoglobulins are produced (synthesized at different rates)

• age 3-4 months = lowest immunoglobulin levels (maternal levels decrease, actively produced antibodies are low

• colostrum = source of antibodies

Describe the components of the adaptive immune response including antigens, antibodies, B and T lymphocytes, agglutination, opsonization and complement fixation and their interactions with each other and macrophages

• Within lymph nodes the antigen is processed by macrophages and presented to T and B cells leading to T cell transformation

• T cell → activated T cell, B cell → plasma cell

• antibody secreted into lymphatic vessels and leave the node, entering blood plasma through the thoracic duct

• stimulation of lymph node = enlargement (reactive or hyperplastic nodes)

• T and B cells = arranged in follicles

Agglutination

• formation large aggregates or clumps of Ag and Ab

• occurs because the two binding sites on antibody molecules cross-link a number of antibody and antigen molecules

• Makes it easier for phagocytes to trap and consume

• Neutralizes toxin

Opsonization

• coating antigen with antibody = increased phagocytosis by leukocytes with receptor for antibody

• Immune phagocytosis seen in unit 3

Complement Fixation

• outcome of complement activation

• Complement = system of 9 plasma proteins (C1-C9) which similar to the clotting cascade, react sequentially

• C56789 or MAC punches holes in cell membranes due to phospholipase activity

• Ag/Ab complex initiates complement cascade = formation of cytotoxic complex and lysis of the cell

  

NOTE: Complement is also associated with the inflammatory response

• C3a and C5a contribute to vasodilation and increased permeability + chemotactic for neutrophils

• C3b acts as opsonin = inducing immune phagocytosis by neutrophils and macrophages

• Agglutination + opsonization occur when the antigenic stimulus is cellular

• Macromolecule = Ag and Ab complexes form a larger macromolecular complex for easy phagocytosis

The formation of immune complexes in vivo lead to:

• inactivation of the antigen or lysis if cellular

• phagocytosis of the antigen by scavenger cells

Outline the mechanisms of the four types of hypersensitivity reactions and give clinical examples of each

Hypersensitivity = state of reactivity in which the immune response leads to tissue injury

TYPE I

Primary vasoactive mediators

• released from mast cell granules and responsible for early events of Type I Hs

Secondary generated lipid mediators

• activated of phospholipase A which acts on mast cell membrane phospholipids to produce arachidonic acid and metabolites

• Increase vascular permeability and chemotactic effects

Cytokine synthesis

• secreted cytokines and chemokines released from mast cells recruit + amplify the response (result in recruitment of inflammatory cells + eosinophils and neutrophils)

Describe the sequence of events that occur in a sensitive individual both on first exposure and on subsequent exposure to the antigen?

First exposure to allergen

• Activation of TH2 cells and IgE class switching in B cells

• Production of IgE

• Binding of IgE to FceRI on mast cells (receptor)

Repeat exposure to allergen

• Activation of Mast cell, release of mediators

  • Vasoactive amines, lipid mediators

    • immediate hypersensitivity reaction

  • Cytokines

    • late phase reaction (2-4 hours)

TYPE II

1. Opsonization and Phagocytosis

   • coated with Ab are opsonized (more susceptible to phagocytosis)

   • Body mistakes normal cell surface component as foreign and reacts against self-antigen

2. Inflammation

   • antibodies activate complement system

   • products recruit neutrophils and monocytes + trigger inflammation in tissues

3. Antibody-Mediated Cellular Dysfunction

   • antibody is formed against cell surface molecule or receptor, inhibiting/stimulating cell function without necrosis

   • Myasthenia gravis = antibodies formed to acetylcholine receptors, binding and rendering non-functional

   • Graves = bind to TSH receptor and stimulate the release of thyroid hormones

TYPE III

• Ab/Ag interaction forms intravascular immune complexes that are deposited in walls of small vessels

• Fibrinoid necrosis of small vessels (Acute vasculitis)

• Formation of immune complexes

• Deposition of immune Complex

• Immune complex-mediated inflammation and tissue injury

Type III causes tissue injury because of the recruitment of neutrophils. Phagocytosis of immune complexes by neutrophils leads to?

Immune complex-mediated inflammation and tissue injury

• depletion of opsonized cells

Why do most forms of Type III hypersensitivity take several days to become clinically apparent?

• takes about 1 week after protein antigen is injected for it to trigger an immune response and the production of antibodies

What are the favored sites for immune complex deposition?

Organs where blood is filtered at high pressure to form other fluids (during and synovial fluid) , glomerulus, and joints

Describe what causes tissue injury following immune complex deposition.

• complement activation and engagement of leukocyte c receptors

Type IV

• mediated by T cells:

  • directly cytotoxic

  • secrete cytokines which recruit other cells and cause injury

1. Delayed-type hypersensitivity is characterized by the presence of?

   CD4+ T cells (cytokine-mediated inflammation)

   CD8+ T cells (direct cell cytotoxicity)

2. Poison ivy dermatitis is a good example of delayed hypersensitivity/ What would happen when a sensitive person undergoes first and second exposure?

   1st = alters self-proteins and neoantigens are recognized as foreign by T cells

3. What is the main cytokine responsible for the development of DTH response?

   CD4 _ T cells → IFN gamma

Differentiate the concepts of self-tolerance, passive and active immunization, primary and secondary immune response

Self Tolerance

Passive Immunization

• Transfer of pre-formed antibody from one person to another (temporary and useful for emergency treatment)

  • Transplacental Immunity = natural acquisition of antibodies across the placenta in utero

  • Colostral Immunity = acquisition of antibodies through colostrum

  • Therapeutic Immunity = medical administration of antibodies against particular agent, toxin, or byproduct to an individual that is known or suspected to have been exposed

Active Immunization

• Development of antibodies in response to an antigen

• Vaccination = artificial active immunization

  • inactive form/altered pathogen is used

  • has antigenicity but not pathogenicity

  • Vaccine acts as primary exposure

• Serology = study of antigen-antibody reactions in lab setting

  • test for antibodies in a patient’s serum

  • Titer = dilution at which Ag/Ab reactivity still occurs

  • Serologic tests used to aid in diagnosis of certain infectious diseases = systemic fungal infections, bacterial infections and viral diseases (measured to determine adequacy of response to vaccine)

Primary Immune Response

• occurs following first exposure to antigen

• lag period between entrance of antigen into body and antibody appearance in the bloodstream

  • B cells with receptors for that antibody undergo clonal expansion

  • IgM first, followed by IgG and other immunoglobulins

Secondary Immune Response (Anamnestic response)

• Accelerated response (no lag period)

• memory = increases response time

• Principal immunoglobulin secreted is IgG (peak is higher and decline is slower than primary response)

Describe how the immune system is involved in transplant rejection, autoimmune diseases and immunodeficiency syndromes

Allograft = graft of tissue between two individuals of the same species with different genotypes

Histocompatibility = function to bind peptide fragments of foreign proteins for presentation to appropriate antigen-specific T-cells

• RBC antigens need to be considered

• Nucleated cell antigens (HLA/histocompatibility antigens)

  • coded for my MHC (major histocompatibility complex) or chromosomal site containing histocompatibility genes

  • Class I = found on all tissues

  • Class II = restricted (presented on antigen-presenting cells)

  • Note the polymorphism at major HLA loci (each individual expresses a unique MHC antigen profile)

T-Cell mediated rejection

Describe how Type IV hypersensitivity (DTH and CTL leads to classic acute rejection)

• CTL’s directed against histocompatibility antigens

• CD8+ CTLs kill antigen-expressing target cells

Antibody-Mediated

How does hyperacute rejection differ from acute antibody-mediated rejection?

• Hyperacute = mediated by preformed antibodies specific for antigens on graft endothelial cells

• Acute = mediated by T cells and antibodies that are activated by alloantigens in the graft

  • acute antibody = antibodies bind to vascular endothelium and activate complement via classical pathway

What characterizes chronic rejection and how does it differ from acute rejection?

Chronic = indolent form of graft damage that occurs over months or years

• manifests as interstitial fibrosis and narrowing of graft blood vessels

• T cells apparently react against graft alloantigens and secrete cytokines

Autoimmune Diseases

• Develops because the clonal deletion phase in embryonic development is somehow faulty so an individual is born with clones of lymphocytes capable of reaction against normal tissue components

• Normally suppressor T cells suppress the clones of lymphocytes for self-antigens

• ANERGY = inactivation of lymphocytes that is induced by exposure to antigens under certain conditions

1. How does immunologic tolerance differ from self-tolerance?

   • Self-tolerance = lack of immune responsiveness to one’s own tissue antigens

   • Immunologic tolerance = unresponsiveness to an antigen that is induced by exposure of antigen-specific lymphocytes

2. When do autoimmune diseases develop?

3. What are the principle mechanisms for inactivation of T cells in central and peripheral tolerance?

   Central tolerance = antigen-induced deletion of self-reactive T lymphocytes and B lymphocytes during maturation in central lymphoid organs

   Peripheral tolerance = Anergy (functional inactivation of lymphocytes that is induced by an encounter with antigens under certain conditions)

   • Suppression by regulatory T cells (the ones responsible for preventing self-reactions)

   • Deletion by apoptosis

4. What is molecular mimicry?

   • Viruses and other microbes might share cross-reacting epitopes with self-antigens

   • Responses indeed by the microbe may extend to self-tissues

Primary Immunodeficiency

Inherited genetic disorders that impair mechanisms of innate immunity (phagocytes, NK cells, or complement) OR humoral and cellular arms of adaptive immunity

SCID = group of genetically distinct syndromes that show defects in both humoral and cell-mediated immunity

1. What age group is primarily affected by SCID and why?

   • infants present with thrush and severe diaper rash

   • maternal T cells transferred across the placenta and attack the fetus

2. SCID is due to impairment of what cell types? How does this differ from defects of innate immaturity

   • impair the development of mature T lymphocytes and or B lymphocytes

   • defects in humoral and cell-mediated immunity

Innate Immunity Defects = affect leukocyte functions or complement system and lead to increased vulnerability to infections

• Leukocyte adhesion deficiencies

• Chronic granulomatus disease

Secondary Immunodeficiency

• occur more frequently than primary immunodeficiencies

AIDS

• retrovirus enters cell, RNA is transcribed into DNA via reverse transcriptase

• Viral DNA integrated into cellular DNA

• IMMUNOSUPPRESSION

• CDR+T cells as well as macrophages and dendritic cells

  • anything that promotes T cell activation will promote the death of HIV-infected cells

  • CD4+ loss = defining characteristic of AIDS

  • death of CDR+ leads to increased susceptibility to viruses, fungi, protozoa and some bacteria

  • Early acute = self-limited illness (virus-specific immune response)

  • chronic phase = HIB is positive but few signs of disease (viral replication continues in lymphoid tissues)