mmi 3713 - unit 5 terms

major macrophage function

• phagocytosis

• antigen presentation

innate immunity

• minutes/hours

• specific for molecules associated with pathogens

• no memory response

• phagocytes, NK cells, dendritic cells

adaptive immunity

• days

• highly specific

• persistent memory

• T cells, B cells, antigen-presenting cells

first line of defense

• skin (epidermis "outside”, dermis)

• mucus membranes

• antimicrobial substances

antimicrobial substances

• lysozymes

• peroxidase

• iron-binding proteins

• defensins

• complement proteins

hematopoiesis

• formation & development of blood cells

• blood cells originate from hematopoietic stem cells found in the bone marrow

general categories of blood cells

• red blood cells (RBC)

  • carry oxygen

• platelets

• white blood cells (WBC)

  • host defense

  • four categories: granulocytes, mononuclear phagocytes, lymphocytes, dendritic cells

macrophages

• part of reticuloendothelial system

• derived from monocytes

phagocyte intracellular killing

• acidification (pH = 3.5 - 4.0)

• antimicrobial peptides

• enzymes

• competitors

toll-like receptors (TLR)

• recognize specific components of foreign invaders

• sends signal to nucleus of cell resulting in gene expression

  • present on phagocytes, endothelial cells, etc.

NOD proteins

• intracellular pathogen-recognition molecule

• recognize bacterial cell wall components

• mutation in protein associated with Crohn’s disease

cytokines

• protein “messages”

  • classes: chemokines, colony stimulating factors, interferons, interleukins, tumor necrosis factor

adhesion molecules

• allows cells to adhere to one another

• responsible for recruitment of phagocytes

complement system

• series of protein circulating in blood & fluids

• initially inactive, stimulation causes ‘cascade’

functions of complement pathway

• cell lysis, bacteria & viruses

• opsonization (preparation for eating) promotes phagocytosis

• trigger specific cell function

• immune clearance

classical pathway (complement cascade)

• antigen-antibody dependent (IgG or IgM)

• part of adaptive response

alternative pathway (complement cascade)

• provides a means of non-specific resistance against infection

• preformed C3b w/ factors B & D

• properdin stabilizes complex

lectin pathway

• 3 proteins: mannan-binding lectin (MBP), and associated serin proteases (MASP and MADSP2)

• MBL: pattern recognition. detects mannan.

complement system

• composed of 9 main proteins (C1-C9)

• some split into C3a and C3b

membrane attack complex (MAC)

• lysis of foreign cells

• creates pores in membrane

• most effective on Gram negative cells

anaphylotoxins

• C4a, C3a, & C5a

• cause basophil/mast cell degranulation & smooth muscle contraction

chemotactic factors

• C5a and C3a

• activate neutrophils, basophils, & macrophages

  • induction of adhesion molecules

opsonins

• C3b & C4b

• attach to CR1 on phagocytic cells & promote phagocytosis

how is unattended activation of complement proteins regulated?

• short half life

• specific host proteins that activate complement proteins

inflammation

• occurs in response to tissue damage

• four signs:

  • heat (calor)

  • pain (dolor)

  • redness (rubor)

  • swelling (tumor)

diapedesis

the passage of blood cells through capillary walls into the tissues

edema

fluid that swells the tissue

• result of increased vascular permeability

rolling & extravasation

1. rolling

2. activation

3. arrest/adhesion

4. transendothelial migration

PMNs first cells to arrive (30 - 60 mins) followed by monocytes + lymphocytes (~56 h)

factors that initiate inflammatory response

• microbial products

• microbial cell surface

• tissue damage

microbial products

• trigger TLR

• causes release of pro-inflammatory cytokines

• synthesis of acute-phase proteins that facilitate complement activation & phagocytosis

microbial cell surface

• produces C3a and C5a

  • mast cell release of pro-inflammatory cytokines & histamine

tissue damage

• enzymatic cascade

• kinin synthesis

  • increased vascular permeability, endothelial cell division, molecule activation, potent nerve stimulators

outcomes of inflammation

• intent is to limit damage & restore function

  • damage is nominal

• consequence of inflammation on systems

  • arthritis

  • meningitis

  • septic shock

fever

• strong indicator of infections

• important host defense mechanism

• stops pathogens by elevating temperature above ideal conditions for growth and activating and speeding up other defenses

apoptosis

• programmed cell death (internal death program)

• cells undergo change to signal macrophages

necrosis

• death of cells of tissues due to chemical or physical injury

• leaves extensive cellular debris to be removed by phagocytes

• induces inflammation

adaptive immunity divided into

• humoral immunity (antibody mediated)

• cellular immunity (T cell mediated)

humoral immunity

• B cell receptors (BCRs)

• membrane-bound derivative of the Ab

• B cells may be triggered to proliferate into plasma cells

• plasma cells produce antibodies

cellular immunity

• mediated by T lymphocytes

• matures in thymus

• two subsets:

  • cytotoxic (CD8+) T cells

  • helper (CD4+) T cells

• T cell receptors (TCR) help with antigen recognition

lymphoid system

• three major functions:

  • concentrate Ag

  • circulate lymphocytes through lymphoid organs

  • carry products of the immune response (Ab and effector cells) to bloodstream and tissues

lymphoid system includes…

• lymphatic vessels

• primary lymphoid organs

• secondary lymphoid organs

lymphatic vessels

• carry lymph to body tissues

• formed as a result of body’s circulatory system

primary lymphoid organs

• bone marrow

• thymus

• where stem cells mature

secondary lymphoid organs

• sites where lymphocytes gather to encounter antigens

• lymph nodes - highly efficient at trapping antigens that enters through afferent lymphatics

• spleen - trap foreign substances in blood

• tonsils

• adenoids

• appendix

antigens

• antibody generator

• big variety of materials

• recognition of antigen directed at antigenic determinant or epitope

nature of antibody

• protective outcomes of antibody-antigen binding

• neutralization

• immobilization and prevention of adherence

• agglutination & precipitation

nature of antibody

• protective outcomes of antibody-antigen binding include:

  • opsonization

  • complement activation

  • antibody-dependent cellular cytotoxicity

antibody-dependent cell-mediated cytotoxicity

• bind to surface antigens on target cells

• various substances secreted by nonspecific cytotoxic cells mediate cell target cell destruction

five classes of Ab

• IgM

• IgG

• IgA

• IgD

• IgE

IgM

• first to respond to infection

• 5-13% in circulation

• pentamer

• highest affinity for complement

• T-independent Ags

IgG

• dominant Ab in circulation

• 80-85% in circulation

• monomer

• can cross placenta. present in colostrum

• MEMORY

IgA

• 10-13% of Ab in circulation; majority in secreted form

• mucosal immunity

• monomer in serum, dimer in secretions

IgD

• <1% total Ab in circulation

• monomer

  • maturation of antibody response

IgE

• barely detectable in circulation

• monomer

clonal selection theory

antigen binds to only one of a multitude of preformed lymphocytes

clonal selection

multiplication of specific antigen-specific lymphocytes

clonal expansion

repeated cycles of cell division generates population of copied antibodies

lymphocyte characteristics

• immature

  • receptor not fully developed

• naive

  • have not encountered antigen

• effectors

  • can produce specific cytokines

• activated

  • can proliferate

• memory lymphocytes

  • remembers antigen on subsequent exposure

antibody diversity

• gene rearrangement

  • maturing B cell selects 3 segments: V,D,J

• imprecise joining

• combinatorial associations

  • specific groupings of light and heavy chains

secondary response

• memory cells responsible for swift reaction

• vaccine exploits immunologic memory

• memory B cells differentiate into plasma cells

T-dependent antigens

evoke immune response only with T helper cells

T-independent antigens

activate B cells without helper T cells

• carbohydrates + lipids

• some polysaccharides & lipopolysaccharides (LPS_

general characteristics of T cells

• multiple copies of T cell receptors

• never produce antibodies

• effectors directly interact with target cells

major histocompatibility complex (MHC) molecule

• MHC class I

  • bind endogenous antigen

• MHC class II

  • bind exogenous antigen

two major functional T cell populations

• cytotoxic T cells

  • CD8 marker

  • MHC class I

• helper T cells

  • CD4 marker

  • MHC class II

giant cell

formed from fused activated macrophages if immune response cannot deal with microbial infection

granuloma

T cells can contain the infection in one to prevent dissemination

lymphocyte development

• B cells undergo development in bone marrow

• T cells undergo development in thymus

clonal deletion

• eliminating lymphocytes that express “self” antigens

• failure of clonal deletion that leads to production of autoantibodies

positive selection

only T cells that recognize MHC are ‘positively’ selected

negative selection

T cells that recognize “self” antigens are negatively selected

natural killer cells

• descend from lymphoid system

• lack antigen specificity

• expression of relatively high levels of class I MHC molecules on normal cells protects them against NK-cell-mediated killing

natural killer cells

• innate immunity

• antibacterial immunity

• response to lipid antigens in tumor cells

type I hypersensitivities: immediate IgE-mediated

• caused by IgE

• immediate reaction of sensitized individual

• sensitization occurs when antigen makes contact w/ some part of body and induces response

type II hypersensitivities: cytotoxic

• IgM antibodies

• complement-fixing antibodies react with cell surface antigens causing cell injury or death

• ex) transfusion reactions (complement fixation), hemolytic disease of newborn (ADCC)

type III hypersensitivities: immune complex-mediated

• immune complexes consist of antigen & antibody bound together

• Fc receptors on cell

• serum sickness

type IV hypersensitivities: delayed cell-mediated

• caused by cell-mediated immunity

• T cells are responsible for reactions

• contact dermatitis, tissue damage, rejection of tissue grafts, and some autoimmune disease

contact dermatitis

small molecules complex with skin proteins that are internalized by APCs in skin, processed, and presented together with class MHC II molecules, causing activation of sensitized Th1 cells

autoimmune diseases

• body recognizes self antigens

• autoimmune diseases may result from reactions to antigens similar to MHC

• may occur after tissue injury

spectrum of autoimmune diseases

• organ-specific (ex. thyroid disease)

• widespread response

  • lupus, rheumatoid arthritis, myasthenia gravis

immunodeficiency disorders

2 types:

• primary or congenital

  • inborn as a result of genetic defect or developmental abnormality

• secondary or acquired

  • can be acquired as a result of infection or other stressor

primary immunodeficiencies

• generally rare

ex. agammaglobulinemia, severe combined immunodeficiency disorder, selective IgA deficiency

secondary immunodeficiencies

• result from environmental, rather than just genetic factors

• often results from depletion of certain cells of the immune system

• most serious & widespread immunodeficiency is AIDS

principles of immunization

• natural occurs from natural events

• artificial or acquired immunity mimics natural events via immunization

active immunity

antibodies are actively being produced

passive immunity

antibodies are already produced

attenuated vaccines

• weakened form of pathogen

  • generally unable to cause disease

• strain replicates in vaccine recipient

• long-lasting immunity

attenuated vaccines

• advantage: induce long-lasting immunity in one dose

• disadvantage: potential to cause disease in immunocompromised individuals. pregnant women should avoid.

• examples of vaccine in use today: sabin polio, MMR, yellow fever

activated vaccines

• unable to replicate in vaccinated individual

• retains immunogenicity

• two categories: whole agents & fragments

detecting interactions

• fluorescent antibody (FA) test

• enzyme-linked immunosorbant assay (ELISA)

• Western blotting

• fluorescense activated cell sorter (FACS)

enzyme-linked immunosorbant assay

• direct ELISA: specific antigen

• indirect ELISA: specific antibody in patient serum

western blotting

• detects antigenic proteins

• proteins separated by size before reacting w/ antibody

• separated by gel electrophoresis

• establishes which proteins recognized by antibodies

fluorescence activated cell sorter (FACS)

• special version of flow cytometry counts cells labeled w/ fluorescent antibodies

• used to count subsets of T cells

• attached to CD4 and CD8 markers