Immunology.txt

• *Hematopoiesis
• *Red Blood Cells
• *Platelets
• *White blood cells

• Formation and development of blood cells.
• Blood cells originate from hematopoietic stem cells found in the bone marrow.

• Also known as erythrocytes
• carry oxygen in blood

• Fragments of megakaryocytes
• important component in blood clotting

• Also known as leukocytes
• important in host defenses
• divided into four categories(granulocytes, mononuclear phagocytes, lymphocytes, dendrititc cells)

• 1.) Neutrophils (55%-65%)
• 2.) Eosinophils (2%-4%)
• 3.) Bsophils (0%-1%), mast cells

• Location : Account for most of the ciculating leukocytes: few in tissues except furing inflammation .
• Functions: Phagocytize and digest engulfed materials.

• Location: Few in tissues except in certain types of inflammation and allergies.
• Functions: Participate in inflammatory reaction and immunity to some parasites

• Location: Basophils in circulation; mast cells present in most tissues.
• functions Release histamine and other inflammation inducing chemicals from the granules

• Monocytes (3%-8%)
• Macrophages

• Location : in circulation; they differentiate into either macrophages or dendritic cells when they migrate into tissue.
• Function: Phagocytize and digest engulfed materials.

• Location: Present in virtually all tissues; given various names based on the tissue in which they are found.
• Functions: Phagocytize and digest engulfed materials

• Location: initially in tissues, but they migrate to secondary lymphoid organs (such as lymph node, spleen, thymus, appendix, tonsils)
• Functions: Gather antigen from the tissues and then bring it to lymphocytes that congregate in the secondary lymphoid organs.

Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterms (PAMPs) thus signaling the presence of foreign invaders or tissue damage.

• 1.) Classical pathway
• 2.) Alternative pathway
• 3.) Lectin pathway

Binding of C3b to cell surfaces (regulatory proteins protect host cell surfaces)

Binding of mannan-binding lectins to cell surfaces

Antigen-antibody complexes.

• Provides a means of non-specific resistance against infection without the participation of antibodies.
• Requires preformed C3b along with factors B and D .
• Properdin helps to stabilize complex.
• Initiates activation of other complement proteins.
• -Short half-life (100us) in fluid phase.
• -Regulation of C3 by serum proteins (DAF, Factor I, factor H)

• –Initiated
• by three proteins: a mannan-binding lectin (MBL), also known as mannan-binding
• protein (MBP) which interacts with
• two mannan-binding lectin-associated serine proteases (MASP and MADSP2),
• analogous to C1r and C1s. This interaction generates a complex analogous to
• C1qrs and leads to antibody -independent activation of the classical pathway.

–MBL

• •Pattern
• recognition molecule

•Detects mannan found on microbial cells

• –Antigen–Antibody dependent (IgG or IgM)
• –Part
• of adaptive response

• •Antibodies
• interact complement C1 (C1qrs)

• –Activates
• protein

• »Leads
• to activation of all complex proteins

• –Activity
• limited by C1-esterase inhibitor (C1INH)

• »Other
• inhibitors of complement pathway to prevent inappropriate activation of
• complement

• •Lysis of foreign cells
• –Complexes
• of C5b, C6, C7, C8 and multiple C9 spontaneously assemble
• •Forms
• donut-shaped structure called membrane attack complex (MAC)
• •Creates pores in membrane
• •Most effective on Gram-negative cells
• –Little
• effect on Gram+ bacteria, due to
• their thick peptidoglycan wall – the MAC cannot get to the membrane

• •Activation of complement leads to major protective outcomes
• •Inflammation
• •Lysis
• of foreign cells (MAC)
• •Opsonization

• Unattended activation of complement proteins
• regulated by short
• half-life of some complement
• proteins and specific
• host proteins that inactivate complement proteins

• inflammation occurs in response to tissue damage.
• There are 4 cardinal signs.
• 1.) Heat(calor)
• 2.) Pain(dolor)
• 3.) Redness (rubor)
• 4.) Swelling (tumor)
• sometimes Loss of function (functio laesa)

• A major difference in the biological
• outcome of inducing apoptosis, necrosis, or pyroptosis is the ensuing
• inflammatory response. Apoptosis is
• generally immunologically silent, while necrosis and pyroptosis are accompanied by secretion of proinflammatory cytokines and the
• extracellular release of the cytosolic content.

•Overview of humoral immunity

–Mediated by B lymphocytes

•a.k.a B cells

–Develops in bone marrow

–B cells carry multiple B cell receptors (BCRs)

• •Membrane-bound
• derivative of the Ab it is programmed to
• make

• –B cells may be triggered to proliferate into
• plasma cells

• •Plasma cells produce
• antibodies

–Antibodies are produced when antigen binds BCR

–Some B cells produce memory cells

• •Overview of cellular
• immunity

–Mediated by T lymphocytes

•a.k.a T cells

–Matures in thymus

–Two predominant subsets

•Cytotoxic (CD8+) T cells

•Helper (CD4+) T cells

• –T cell receptors (TCR) help with antigen
• recognition

•Primary lymphoid organs

• –Bone marrow and thymus are primary lymphoid
• organs

• •Location where stem
• cells destined to become B and T cells mature (pick up their BCRs or TCRs)

• –B cells mature in bone
• marrow (prior to birth in fetal liver)

• –T cells mature in
• thymus

• •Once mature, cells
• leave primary lymphoid organs and migrate to secondary lymphoid organs where
• they wait to encounter antigen

• •Word comes from
• compounds that elicit antibody production

–Antibody generator

• •Includes an enormous
• variety of materials

• •Today, term used to
• describe any compound that reacts specifically with an Ab or an Ag receptor on a lymphocyte

–Ag may not elicit an immune response (immunogens elicits IRs)

• –Substances w/ MW < 10,000 da typically not
• immunogenic

• •Proteins and
• polysaccharides induce strong responses

–Lipids and nucleic acids often do not

• •Recognition of antigen
• directed at antigenic determinant or epitope

•Five classes of Ab


–IgM

• •First Ab to respond to
• infection

•5 – 13% of Ab in circulation

•Structure: pentamer

• –Five monomer units
• joined together at the constant region

• –Primarily involved in
• control of bloodstream infections

• •Found on the surface
• of B lymphocytes as a monomer

• •Most efficient at
• eliciting “classical” complement cascade (highest affinity for complement)

• •Effective in
• agglutination and precipitation reactions

• •Only class produced
• during immune responses to T-independent Ags

• •Only Ab that can be formed by
• the fetus if infected in utero (IgM production gen. begins after birth)

•Clonal Selection Theory

• –Antigen bind to only one of a multitude of
• preformed lymphocytes

• •Initiates multiplication of specific
• antigen-specific lymphocytes

–Process called clonal selection

• –Repeated cycles of cell division generates
• population of copied antibodies

»Termed clonal expansion

• •Without sustained
• stimulation, cells undergo apoptosis curtailing the immune response

• •Lymphocyte
• characteristics include

–Immature

• •Have not fully developed their antigen specific
• receptor

–Naïve

• •Have antigen receptor but have not encountered
• antigen

–Activated

•Able to proliferate

•Have bound antigen

–Effectors

•Descendents of activated lymphocytes

•Able to produce specific cytokines

•Plasma cells, T helper and cytotoxic T cells effector cells

–Memory lymphocytes

•Long-lived descendents of activated lymphocytes

• •Memory cells responsible for speed and
• effectiveness of secondary response

• –Remembers antigen on
• subsequent exposure

• •In many cases B cell
• needs confirmation from T helper cells

•Co-stimulatory or second signal

• •TH cell releases cytokines that activates B cells to divide and
• differentiate

–Produce plasma cells and memory B cells

• –If the T cell does not
• recognize the Ag the immune response may become “tolerant” to that antigen

•Diversity involves

–Gene Rearrangement

• •Maturing B cell
• selects 3 segments

–V-D-J

–Imprecise Joining

• •Nucleotides deleted or
• added

–Combinatorial Associations

• •Specific groupings of
• light and heavy chains

Alpha chain, Beta chain, Antigen: MHC-binding site

• –During antigen
• presentation, antigen cradled in grove of major histocompatability complex molecule (MHC molecule)

•Two types MHC

• –MHC
• class I

»Bind endogenous antigen

• –MHC
• class II

»Bind exogenous antigen

–Two major functional T cell populations

•Cytotoxic T cells

• –Proliferate and differentiate to destroy infected
• or cancerous “self” cells and in graft rejection

–Have CD8 marker

• –Recognize MHC
• class I

•Helper T cells (orchestrate immune response)

• –Multiply and develop into cells that activate
• cell mediated immune responses and macrophages (Th1-type) and humoral (B cells)
• responses (Th2-type)

–Stimulate other T cells

–Have CD4 marker

–Recognize antigen displayed by MHC class II

• –Induce apoptosis in “self” cells and graft
• rejection

• •Cells infected with virus or intracellular
• microbe

•Destroys cancerous “self” cells

•Foreign cells involved with graft rejection

• –Nucleated target cells degrade portion of
• proteins

•Load peptides into groove of MHC class I molecule

•MHC class I molecule recognized by circulating Tc cell

–Cell destroyed by lethal effector function of Tc cell

•Tc cells releases pre-formed cytotoxins (perforin and other proteases such as granzymes) that induces cell lysis or apoptosis

• •Can induce apoptosis via binding of FasL (Fas Ligand) on activated CD8 T
• cell to Fas on the target cell

–Secretes cytokines

• –Macrophages routinely
• engulf invading microbes resistant to lysosomal killing

• –TH cells “activate” macrophages by delivering cytokines that
• induce more potent destructive mechanisms

• –If immune response can
• not deal with the microbial infection, activated macrophages can fuse to form a
• multinucleated giant cell and together with
• other macrophages, PMNs, and T cells can contain the infection within a granuloma thus preventing dissemination of the infection

• •During lymphocyte development, B and T cells acquire ability to
• recognize distinct epitopes

• –Once committed to
• specific antigen, cells “checked out” to ensure proper function and that they
• do not respond to self antigens

–B cells undergo developmental stages in bone marrow

–T cells go through process in thymus

•Negative Selection

• –Process of eliminating lymphocytes that express
• “self” antigens (clonal deletion)

–Failure of clonal deletion leads to production of autoantibodies


–B cell w/ BCR is exposed to Ags w/n bone marrow and all that bind “self” antigens undergo apoptosis

• –Naïve B cells that recognize Ag in secondary lymphoid tissues are eliminated if they do not receive second
• signal from T helper cell

•Occurs in thymus

•Positive Selection

• –Only those T cells that recognized self MHC is
• “positively” selected

•TCR recognizes a peptide:MHC complex

•Negative Selection

• –T cells that recognize “self” antigens are
• negatively selected

• •Very small part of T
• cell population in the periphery (3-5% of T cells)

• •Most evidence suggests
• that they do not require either MHC processing or presentation of antigen in
• context of MHC

• –Present glycolipids, phospholipids, and some protein ags that are neither
• processed or presented in the context of MHC

•More of a role in innate immunity

–Role is similar to a PRR

• –May kill infected cells or organisms using
• mechanisms similar to those of CTLs (granulysin and perforin)

–Secrete cytokines and chemokines

•Natural killer cells descend from lymphoid stem cells

–They lack antigen specificity

•No antigen receptors

•Memory? (maybe)

• –Mediate lysis of host cells altered
• by stress, viral infection, or transformed into tumor cells (these cells
• express less class I MHC)

• –Killing is regulated
• by the balance b/w positive signals generated by the engagement of activating
• receptors and negative signals from inhibitory receptors

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

•Characteristics common to both T cells and NK cells

–T-cell receptor invariant

• •TCRa and TCRb chains encoded by
• specific gene segments

• –TCR on NKT cells does not recognize MHC-bound peptides but rather a glycolipid presented by another
• molecule (CD1d)

–NKT cells do not form memory cells

• –Expresses a number of
• markers that are characteristic of NK cells but not T cells

•Involved in innate immunity

–Antibacterial immunity

• –Response to lipid
• antigens specific to tumor cells