Lecture 1 review

Self vs. Non-Self Recognize self Recognize the absence of self Recognize non-self Pattern recognition receptors Somatically generated receptors

The innate vs. adaptive immune systems (5) First response time Immediate activation of effectors; minutes to hours Activation only requires a single signals Response by actual activated cell Long response times; Days-weeks Multiple permissive signals required Stimulated cell can undergo clonal proliferation. Amplified immune responses. Response to repeat stimuli Quick, but identical to primary response Much more rapid than primary responses. Generation of robust “memory” Major components   Physical barriers Phagocytes Granulocytes Pattern recognition molecules T and B cells Antigen-specific receptors Antibodies

DIVERSITY OF RECEPTORS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS

Antigen – collection of ligands recognized by cells of both the innate and adaptive immune systems Epitope – smallest individually identifiable part of an antigen that is bound by a receptor

Innate Pattern Recognition Receptors How innate immune cells distinguish between microbes and self-cells? How do they “know” if something is “dangerous” or not? (i.e. food, commensal organisms in the mouth and gut) Use sets of highly conserved receptors that recognize patters of molecules shared by microbes – Pathogen-Associated Molecular Patterns (PAMPS)

Hematopoietic Lineages

Cytokines of Innate Immunity Interleukins – produced and act on leukocytes Chemokines – direct cell movement TNF, IL-1 - active vessels and recruit Neutrophils IL-1 – Fever IL-6 – Acute phase response

Inflammation and local response Activated innate cells trigger the process of inflammation: Dolor (pain) Calor (heat) Rubor (redness) Tumor (swelling) Functio laesa (Loss of function; Immobility)

Inflammation and local response Release of vasodiolators = increased blood flow (rubor) and heat (calor) Altered permeability (edema) = leakage of plasma proteins containing complement components, CRP, MLB, clotting factors Leads to production of inflammatory cytokines (IL-1, TNF by macrophages) that trigger a whole range of effects designed to Recruit other cells to the site

Local vs. systemic responses by innate immune system Local inflammatory response can be mild, short-lived May not even involve adaptive immune response If infection is not contained, leads to systemic response, with more extensive consequences

Natural Killer Cell Recognition

Big picture: local innate immune responses

Big picture: local innate immune responses

Big picture: innate cell initiation of adaptive immune responses http://www.proteinlounge.com/Animation/Immune%20Response,%20Toll%20Like%20Receptors%20(TLR)%20Pathway

Adaptive Immune System 1 E1542 Biomedical Science Tower Immunology - Lecture 2 Adaptive Immune System 1 Heth R. Turnquist, PhD E1542 Biomedical Science Tower 200 Lothrop Street turnquisthr@upmc.edu

Molecules of the Adaptive Immunity - 6

Adaptive Immune System The adaptive immune system uses a broad range of molecules to function. Some of the molecules used by the adaptive immune system are also used by the innate immune system. Other molecules are specific to the adaptive immune system. B cell receptor (antibodies) T cell receptor i.e. Ag – receptors CD (Cluster of differentiation Molecules) – CD3, CD4, CD8, etc

Immunoglobulins Synthesized by B lymphocytes (B cells) Synthesized and secreted by plasma cells – terminally differentiated B cells Antibody is an immunoglobulin molecule with specificity for an epitope of an antigen. Antibodies facilitate cells and molecules in the immune system to identify and interact with antigens. Soluble antibodies are components of humoral (soluble) immune responses.

Immunoglobulin (Ig) Basic structure: -4 polypeptide chains 2 Heavy Chains 2 Light Chains -Called Ig Monomer Variable domains on HC And LC form epitope Binding domain Epitope = part of Ag Fc - Region

Ig Monomers Contain 2 identical light chains and two identical heavy chains Binding site for each monomer is identical Diversity generated by different pairings of heavy and light chains

Properties and Biological Activities of Immunoglobulin Isotypes Property/Function IgG IgA IgM IgE IgD Heavy chain g a m e d Highest concentration in serum √ Activates complement Crosses placenta Present on B cell membrane Binds to receptors on phagocytes Involved in mucosal immunity Mast cell degranulation IgM IgD IgG IgA IgE

Ig and Complement Cascade (1) Interaction of antibody with antigen activates the classical complement pathway. Ag binding to epitope on Ag = change in Ab Fc region = C1q,r,s binding C1 components activate cascade culminating in MAC formation and cell lysis

Ig and Complement Cascade (2) Interaction of antibody with antigen activates the classical complement pathway. Ag binding to epitope on Ag = change in Ab Fc region = C1q,r,s binding C1 components activate cascade culminating in MAC formation and cell lysis

Major Histocompatibility Complex (MHC) Tightly linked cluster of genes in all mammals Called Human Leukocyte Antigen (HLA) complex Gene products (3 classes) play a role in Intercellular recognition Discrimination between self and nonself Important in cellular and humoral immunity Acts as antigen presenting structures The particular set of MHC molecules expressed by an individual influences the repertoire of Ag to which individual T cells can respond May have a role in susceptibility to disease and in development of immunity On Chromosome 6

MHC Class I, II, and III Located on Chrom 6; Human Leukocyte Antigen

MHC Class I, II, and III Located on Chrom 6; Human Leukocyte Antigen

2 Types of MHC MHC class I – expressed on all nucleated cells MHC class II – expressed on APCs

T Cell Receptor (TCR) T cells – each T cell expresses a unique, epitope specific cell surface receptor Heterodimers of two polypeptide chain Lack the capacity to initiate signaling to the nucleus capacity and rely on CD3 to transmit signals Unlike Ab – can not bind soluble Antigens. See peptides in context of MHC

Two subsets of T cells interact differently with MHC: CD4+ T cells only interact with peptides bound to MHC class II CD8+ T cells only interact with peptides bound to MHC class I

Cells and Organs - 7

Lymphocytes All originate from bone marrow Named after place of “education” Thymus-derived cells = T cells (CD3+ TCR+) CD4+ T cells CD8+ T cells Bone-marrow-derived cells = B cells (BCR+ CD19+) B cells – BCR+ cells Plasma cells – terminally differentiated B cells producing Ig and no longer displaying it on surface Natural Killer Cells (CD3- BCR- CD56+) Granular appearance due to perforin and granzyme Develop in BM – no education in Thymus

CD4+ T cells Comprise two thirds of all T cells Recognize antigen in complex with Class II MHC molecules Provide helper function

CD8+ T cells Comprise one third of all T cells Recognize antigen in complex with Class I MHC molecules Potent cytotoxic functions “Cytotoxic T cells”

B cells Mature in the bone marrow Express membrane bound antibody (Ig) on surface Recognize soluble antigen

When Ab on the surface of a B cells binds antigen for the first time, the B cell begins to divide rapidly to become a Plasma cell – secretes antibody; Small amount of membrane Ab; life span of a few days Or Memory cell – identical membrane antibody as on parent B cell, longer life span

Natural Killer (NK) and Natural killer T (NKT) cells bridge the innate and adaptive Immune systems. NK Cells Granular lymphocytes No expression of TCRs No expression of BCRs Express receptors for: 1. Stress molecules (KARs) 2. MHC class I molecules (KIRS) NK T cells Express low levels of TCRs with limited repertoires

Lymphoid tissues and organs - Primary Lymphoid organs Primary Lymphoid organs – Place where T and B cells learn to see self from non-self Thymus: Bilobed organ where“prothymoctyes” from bone marrow turn into T cells Where T cells aqcuire CD4, CD8, TCR Self reactive cells removed

Thymic Education of T cells

Lymphoid tissues and organs - Primary Lymphoid organs Bone Marrow: lymphocytic lineages that become B cells stay and undergo differentiation here If early IgM on surface recognizes “self” they undergo apoptotic death

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs Lymphatic circulatory system Cardiovascular system is responsible for circulating the soluble and cellular components of the immune system Collection/filtration in the spleen

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs Lymphatics – Extensive capillary network that drains the tissues and collects lymph Lymph = watery clear fluid that contains leukocytes and cells debris Drainage system to remove cellular debris and microbes from the body’s tissues to the lymph nodes

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs Spleen – Largest lymphoid organ Clears particulate from blood Concentration of Ag and microbes Lots of T cells and B cells (making antibody) Lots of Macrophages – dead cell removal

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs Lymph nodes – places of leukocyte accumulation and lymph filtration

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs Mucosa associated lymphoid tissues (MALT)

Lymphoid Organs and Tissues Primary Lymphoid Organs Secondary Lymphoid Organs and Tissues Thymus Bone Marrow Spleen Lymph nodes Mucosa-associated lymphoid tissues (MALT) Tonsils Appendix Peyers’s patches