Lecture 1 review. Self vs. Non-Self Recognize self Recognize the absence of self Recognize non-self – Pattern recognition receptors – Somatically generated.

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)

Innate Adaptive

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 ligandsrecognized by cells of both the innate and adaptive immune systems

Epitope – smallest individuallyidentifiable 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

Immunology - Lecture 2Adaptive Immune System 1

Heth R. Turnquist, PhDE1542 Biomedical Science Tower

200 Lothrop [email protected]

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 epitopeBinding 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

Property/Function IgG IgA IgM IgE IgDHeavy 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 √

Properties and Biological Activities of Immunoglobulin Isotypes

IgE

IgA

IgG

IgD

IgM

Interaction of antibody with antigenactivates 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 (1)

Interaction of antibody with antigenactivates 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)

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

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 – expressedon 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 ofa 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 adaptiveImmune 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

• 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

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

• Lymph nodes – places of leukocyte accumulation and lymph filtration

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs

• Mucosa associated lymphoid tissues (MALT)

Lymphoid tissues and organs – Secondary Lymphoid tissue and organs

Lymphoid Organs and TissuesPrimary Lymphoid Organs

Secondary Lymphoid Organs and Tissues

ThymusBone Marrow

SpleenLymph nodesMucosa-associated lymphoid tissues (MALT)TonsilsAppendixPeyers’s patches