immune_receptors

SECRETED EFFECTOR MOLECULES AND MEMBRANE BOUND RECEPTORS

COMPOSED OF 4 POLYPEPTIDE CHAINS JOINED BY DISULFIDE BONDS

2 IDENTICAL PAIRS OF HEAVY AND LIGHT CHAINS

IgM – FIRST PRODUCED BY MATURE B-CELLS

IgD

IgG

IgE

IgA

FIRST 110 AMINO ACIDS IN AMINO TERMINAL SEQUENCE

INVOLVED IN ANTIGEN BINDING

1

2 HEAVY CHAIN FRAGMENTS

NO ANTIGEN BINDING ACTIVITY

FLEXIBILITY BETWEEN Fab AND Fc

PROLINE RICH

PROTEASE SINSITIVE

MOST INTER-CHAIN DISULFIDES ARE FOUND HERE

DETERMINES AVAILABILITY FOR ANTIGEN BINDING BASED ON STERIC CONSIDERATIONS

4 OR 5 SIMILAR DOMAINS OF 110 AMINO ACIDS EACH

EACH DOMAIN CONTAINS ONE INTRA-CHAIN DISULFIDE LINKAGE THAT IS IMPORTANT FOR TERTIARY STRUCTURE

COMPEMENTARITY DETERMINING REGIONS

SPECIFIC REGIONS THAT SHOW STRUCTURAL VARIABILITY KNOWN AS HYPERVARIABLE REGIONS

3 CDRs FOR EACH HEAVY AND LIGHT CHAIN, 6 ON EACH ARM; 12 TOTAL

LINE THE SHALLOW GROVE FORMED BY THE APPOSITION OF THE 3-STRANDED B-SHEETS MAKE UP THE HEAVY/LIGHT CHAINS THAT FORM ANTIGEN BINDING SITE

AFFINITY IS A THERMODYNAMIC VALUE THAT QUANTIFIES THE STRENGTH OF ANTIBODY BINDING TO AN ANTIGENIC DETERMINANT

AVIDITY IS THE OVERALL INTERACTION STRENGTH OF 2 OR MORE ANTIBODIES BINDING TO ANTIGENS AND IS OFTEN GREATER THAN SUM OF INDIVIDUAL ANTIBODY AFFINITY

EARLIEST STAGE OF B-CELL DIFFERENTIATION

LYMPHOID PROGENITORS

ANTIGEN-INDEPENDENT

FROM PRO-B CELLS

FIRST TO EXPRESS Ig HEAVY CHAIN IN CYTOPLASM

M-HEAVY CHAIN IS SYNTHESIZED FIRST BEFORE LIGHT CHAIN

ANTIGEN INDEPENDENT

FROM PRE-B CELLS

LIGHT CHAIN SYNTHESIS AND ASSEMBLY WITH HEAVY CHAINS FORMING COMPLETE IgM ANITBODY MOLECULE THAT IS EXPRESSED ON CELL SURFACE

ANTIGEN INDEPENDENT

FROM IMMATURE-B CELLS

B CELL BEGINS TO EXPRESS BOTH IgM AND IgD ON SURFACE, EACH EXPRESSING THE EXACT SAME VARIABLE REGION AND THUS SAME SPECIFICITY FOR ANTIGEN

MONOSPECIFIC

MATURE B-CELLS ACTIVATED BY SPECIFIC ANTIGEN

BEGIN TO SECRETE IgM

HEAVY CHAIN CLASS SWITCHING, EXPRESSION OF OTHER ANTIBODIES

PLASMA CELLS

MEMORY CELLS

CONTAIN LOTS OF RER AND SECTRETE ANTIBODY AT VERY HIGH RATE/QUANTITY

DON’T EXPRESS MEMBRANE FORM OF ANTIBODY

END STAGE OF B-CELL DIFFERENTIATION

ANTIGEN DEPENDENT

LONG-LIVING LYMPHOCYTES RESPONSIBLE FOR SECONDARY RESPONSE

USUALLY EXPRESS ISOTYPES OTHER THAN IgM ON SURFACE

ANTIGEN DEPENDENT

PRE-B CELLS

PRO-B CELLS --> PRE-B CELLS

PLASMA CELLS

MEMORY CELLS?

VARIABLE REGIONS ENCODED BY MULTIPLE GENE SEGMENTS

GENE REARRANGEMENT DURING ANTIGEN-INDEPENDENT PHASE

4 GENE SEGMENTS ON CHROM 14 – V,D,J,C

D --> J

THEN V --> DJ TO FORM M-HEAVY-CHAIN GENE

M-HEAVY-CHAIN GENE EXPRESSED FIRST AND MEMBRANE FORM ACTIVATE K-LIGHT-CHAIN REARRANGEMENT

EACH PROTEIN DOMAIN INCLUDING HINGE, TAILPIECE, TRANSMEMBRANE, AND CYTOPLASMIC IS ENCODED BY A SEPARATE EXON IN THE FUNCTIONALLY ASSEMBLED CHAIN

D --> J MUST BIND FIRST

UNABLE TO FORM MATURE-B CELLS OR T-CELLS

NO ADAPTIVE IMMUNITY

Decrease the overall diversity of antibodies because of the lack of the recombination mechanism

Ig GENE REARRANGEMENT (V,D,J COMBOS)

HEAVY/LIGHT CHAIN COMBOS

JUNCTION DIVERSITY

IMPRECISE JOINING OF V,D,&J SEGMENTS

GREATER DIVERSITY

BUT OFTEN LEAD NON-PRODUCTIVE REARRANGEMENTS DUE TO READING-FRAME SHIFTS

ALTERNATIVE RNA TERMINATION

PROCESSING OF LONG RNA TRANSCRIPT

IgM AND IgD DIFFERENTIALLY REGULATED DURING B-CELL MATURATION

IgD LEVEL ON SURFACE OF IMMATURE B CELLS IS LOW OR ABSENT

MATURE-B CELLS HAVE HIGHER DENSITY OF IgD RELATIVE TO IgM

BOTH ARE EXPRESSED FROM SAME TRANSCRIPTION UNIT

MIg CONTAINS A HYDROPHOBIC TRANSMEMBRANE REGION AND A CYTOPLASMIC TAIL SEQUENCE AT THE CARBOXYL END

SEPARATE EXONS ENCODE SECRETED OR MEMBRANE-BOUND ENDS

REGULATED BY ALTERNATIVE RNA PROCESSING EVENTS INVOLVING CHOICE OF 2 DIFFERENT RNA

CLEAVAGE AND POLY-A SITES

EXPRESSION OF A GENE FROM ONLY ONE OF TWO PARENTAL CHROMS

MUST FOLLOW SEQUENCE OF “IF/THEN” STEPS, i.e. IF FIRST CHROM MAKES NON-PRODUCTIVE PROTEIN THEN 2ND CHROM IS ACTIVATED.

3 HIGHLY VARIABLE REGION DOMAINS THAT CORRESPOND TO THE CDRs FOUND IN Ig

V, D, J, AND C REGION GENES SIMILAR TO Ig HEAVY CHAIN

JUNCTIONAL DIVERSITY – CONTRIBUTES MORE TO TCR DIVERSITY THAN IN Ig. N & P NUCLEOTIDE ADDITION OCCURS BOTH IN ALPHA & BETA CHAINS, D REGIONS CAN OFTEN BE TRANSLATED IN ALL 3 READING FRAMES

ASSOCIATION OF DIFFERENT ALPHA AND BETA CHAINS

NO SIGNIFICANT SOMATIC MUTATION IN TCR GENES

T CELLS USUALLY ONLY RECOGNIZE PROTEIN ANTIGENS

2 CLASSES OF TCRs (T-CELL RECEPTORS), ALPHA-BETA AND GAMMA-DELTAHETERODIMER

SIMILAR TO Ig

BOTH ARE DISULFIDE LINKED WITH VARIABLE, CONSTANT, TRANSMEMBRANE AND CYTOPLAMIC REGIONS

BCRs HAVE HEAVY/LIGHT CHAIN INTERACTIONS WHILE TCRs HAVE ALPHA-BETA ACIDIC-BASIC CHAIN INTERACTIONS

TCRs ARE MEMBRANE-BOUND ONLY

ALPHA-BETA T CELLS ONLY RECOGNIZE ANTIGENS ASSOCIATED WITH MHC MOLECULES

GAMMA-DELTA T CELL FUNCTION IS NOT KNOWN AND IS 10% OF MATURE PERIPHERAL T-CELL

CD3 COMPLEX (CD GAMMA, DELTA, AND EPSILON)

ZETA PROTEIN LOCATED ON THE CYTOPLASMIC SIDE

SERVE TO TRANSMIT SIGNALS TO THE INTERIOR OF THE CELL ONCE THE TCR ENGAGES ANTIGEN

1) CTL MUST BE ACTIVATED. ANTIGEN MUST BE PROCESSED BY PROTEOSOMES INTO SMALL FRAGMENTS AND PRESENTED TO CTLs BY APCs (DENDRIDIC, MACROPHAGES, B CELLS)

2) ACTIVATED CTL MUST TARGET INFECTED HOST CELLS (AND DISREGARD NONINFECTED CELLS) BY REGOGNIZING BOTH THE ANTIGEN AND MHC I RECEPTORS

DEGRADE INTRACELLULAR PROTEINS

UPREGULATED BY CYTOKINES (IFN-GAMMA)

PROTEINS TAGGED WITH UBIQUITIN ARE RAPIDLY DEGRADED AND PASSED INTO ER BY TAP 1&2

MHC I RECEPTORS STICK TO TAB BY TAPSIN, WHERE THEY ARE PLACED INTO CLOSE PROXIMITY TO FRAGMENTS ENTERING THE ER

HEAVY CHAIN CONSISTINGOF 3 EXTRACELLULAR SEGMENTS (ALPHA 1,2&3), A MEMBRAIN SEGMENT, AND A CYTOPLASMIC SEGMENT

BETA-2 MICROGLOBULIN NONCOVALENTLY ASSOCIATED WITH, AND NOT GENETICALLY ENCODED WITH, THE HEAVY CHAIN. MHC I CANNOT BE EXPRESSED WITHOUT B-2 MICROGLOBULIN

NO RECOMBINATION AT THE DNA LEVEL

ANTIGEN BINDS TO ALPHA 1&2 ON HEAVY CHAIN

POLYGENIC, CONSISTING OF 3 ISOFORMS (A,B,&C) OF HEAVY CHAIN

POLYMORPHIC, HUNDREDS OF ALLELES IN THE HUMAN POPULATION FOR THE 3 ISOFORMS A,B,&C.

CO-DOMINANT EXPRESSION (ex. 2 FORMS OF B ISOFORM WILL BE EXPRESSED IF HETEROZYGOUS)

TCRs REQUIRE AN ADDITIONAL COMPLEX (CD3) FOR CELL ACTIVATION

TCRs MUST ALSO HAVE DUAL RECOGNITION. THEY MUST BIND BOTH TO THE ANTIGEN AND TO THE ALPHA HELICAL COMPONENTS OF THE MHC RECEPTOR

SIGNAL 1 REQUIRES DUAL RECOGNITION BY TCRs OF BOTH ANTIGEN AND MHC I RECEPTOR. ALSO, THIS BINDING REQUIRES CO-RECEPTOR CD8 EXPRESSED BY T-CELL WHICH BINDS TO ALPHA 3 OF MHC CHAIN. CD3 THEN TRIGGERED, COMPLETING SIGNAL 1

SIGNAL 2 INVOLVES CO-STIMULATORY MOLECULES (CD28 ON T-CELL AND CD80/86 (B7) ON APC)

SIGNAL 1 IN ABSENCE OF SIGNAL 2 CREATES ANERGY

ONCE ACTIVATED, T-CELLS DO NOT NEED SIGNAL 2

THE CYTOKINE INTERLEUKIN 2 (IL-2) IS REQUIRED FOR GROWTH AND ALSO SUSTAINED ACTIVATION

PRODUCED BY CD4 SUBSET CELLS TH1

CASPASE AND CASPASE-ACTIVATED DNase (CAD) CAUSE DNA FRAGMENTATION

GRANZYMES ARE CYTOPLASMIC GRANULES WHICH MIGRATE TOWARD TARGET CELL AFTER BINDING AND ENTER THROUGH PORES CREATED BY PERFORIN AND ENTER INTO CASPASE PATHWAY

PERFORIN INCALATES INTO THE LIPID BILAYER OF PLASMA MEMBRANE TARGET CELL CREATING LARGE PORES

FAS LIGAND EXPRESSED ON CTLs IS RELATED TO THE CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-A). AFTER DUAL RECOGNITION, FAS LIGAND ENGAGES FAS ON TARGET CELL AND INITIATES CASPASE CASCADE

CONSIDERED PART OF THE INNATE DEFENSE SYSTEM

CONTAIN MANY CYTOPLASMIC GRANULES AND ARE SOMETIMES REFERED TO AS LARGE GRANULAR LYMPHOCYTES (LGLs)

DO NOT RECOGNIZE ANTIGENS AND PREFERENTIALLY ATTACK HOST CELLS THAT LACK MHC I RECEPTORS.

1) APC TO PROCESS AND PRESENT EXTRACELLULAR ANTIGENS VIA MHC II RECEPTORS

2) HELPER T-CELLS TO UPREGULATE B-CELLS AND THUS PLASMA CELLS

1) PHAGO/ENDOCYTOSIS OF ANTIGEN

2) FUSION OF VESICLE WITH LYSOSOMES

3) FUSION OF VESICLES CONTAINING DIGESTED FRAGMENTS AND VESICLES CONTAINING MHC II RECEPTORS FROM GOLGI

4) PARTIAL DIGESTION OF INVARIANT CHAIN PLUGGING UP MHC II LEAVING CLASS II ASSOCIATED INVARIANT CHAIN PEPTIDE (CLIP)

5) CLASS II MOLECULE HLA-DM REMOVES CLIP AND ALLOWS BINDING OF ANTIGEN AND MHC II

2 ALPHA AND 2 BETA SEGMENTS CREATING HETERODIMER

ALPHA 1 AND BETA 1 PROVIDE SITE FOR ANTIGEN BINDING

3 ISOFORMS (HLA-DP, HLA-DQ, AND HLA-DR)

ALPHA CHAINS FOR DP, DQ, AND DR

BETA CHAINS FOR DP, DQ, AND 2 FOR DR

DIMER CREATED FROM 1 ALPHA AND 1 BETA CHAIN

NO RECOMBINATION

WITH 2 BETA DR FORMS, MHC II HAS TOTAL OF 8 DIFFERENT POTENTIAL MOLECULES COMPARED TO 6 MHC I

IL-2 SUPPORTS T-CELL GROWTH AND SUSTAINED ACTIVATION

IFN-GAMMA ENHANCES INFLAMMATION, ACTIVATES PHAGOCYTES, SUPPRESSES TH2 RESPONSES. PROMINENT PRODUCT OF NK CELLS, WHICH AMPLIFIES TH1-CELL ACTIVATION AND DAMPENS TH2-CELL ACTIVATION

TNF-ALPHA ENHANCES INFLAMMATION, INCREASES VASCULAR PERMIABILITY

IL-3 STIMULATES HEMATOPOIESIS

IL-3 STIMULATES HEMATOPOIESES

IL-4 B-CELL ACTIVATION AND GROWTH, IgE ISOTYPE SWITCH, SUPPRESSES TH1/TH17 RESPONSES

IL-5 B-CELL DIFFERENTIATION, SUPPRESSES PRODUCTION OF TH1 CYTOKINES

IL-10 B-CELL DIFFERENTIATION, SUPPRESSES PRODUCTION OF TH1 CYTOKINES

TGF-BETA B-CELL DIFFERENTIATION, SUPRESSES PRODUCTION OF TH1 CYTOKINES

*THINK EXTRACELLULAR RESPONSE

IL-17 INDUCES CHEMOKINES FOR NEUTROPHIL RECRUITMENT, INDUCES IL-6, INDUCES ACUTE PHASE PROTEINS, SYNERGIZES WITH IFN-GAMMA AND TNF-ALPHA

MACROPHAGES

INITIAL STAGES OF T-CELL GROWTH, FEVER

MACROPHAGES & T CELLS

GROWTH AND DIFFERENTION OF NUMEROUS LEUKOCYTES, PROMINENT IN INDUCTION OF ACUTE PHASE PROTEINS

DENDRITIC CELLS AND MACROPHAGES

STIMULATES NK CELLS TO PRODUCE IFN-GAMMA

INHIBITS TH17 DIFFERENTIATION

IL-23 PROMOTES TH17 DIFFERENTIATION

DENDRITIC CELLS

STIMULATES TH17 CELLS TO PRODUCE IL-17

TUMOR NECROSIS FACTOR

MACROPHAGES, NK CELLS, TH1 CELLS

ENHANCES INFLAMMATION, INCREASES VASCULAR PERMEABILITY, CYTOTOXIC FACTOR

MACROPHAGES, T-CELLS

STIMULATES GROWTH AND DIFFERENTIATION OF MYELOID LINEAGE

ASSOCIATED WITH VARIETY OF CAUSES INCLUDING INFECTION

SEPSIS SYNDROME IS EXCESSIVE RELEASE OF INFLAMMATORY MEDIATORS DUE TO INFECTION REULTING IN ENDOTHELIAL DAMAGE, HYPOTENSION, POORLY REGULATED COAGULATION THAT CAN LEAD TO IRREGULAR HEARTBEAT (TACHYCARDIA), AND EVENTUAL MULTI-ORGAN FAILURE

ASSOCIATED WITH DISSEMINATED INTRAVASCULAR COAGULATION RELATED TO BACTERIA

SEPTIC SHOCK

PRODUCED BY MICROBIAL PATHOGENS THAT ACTIVATE LARGE NUMBERS OF T CELLS WITH PRO-INFLAMMATORY CAPABILITIES (ex TH1/TH17 CHARACTERISTICS)

RESPONSIBLE FOR A VARIETY OF CLINICAL CONDITIONS ASSOCIATED WITH SHOCK, INCLUDING TOXIC SHOCK SYNDROME AND FOOD POISONING

ACTIVATE T CELLS INDEPENDENT OF THEIR ANTIGEN SPECIFICITY DUE TO BINDING OUTSIDE OF POLYMORPHIC ANTIGEN BINDING REGIONS

CLUSTER OF INFECTED MACROPHAGES WHICH ARE WALLED OFF BY T CELLS (ex MYCOBACTERIUM TUBERCULOSIS)

MIROORGANISMS WHICH ARE ABLE TO SURVIVE INGESTION INTO PHAGOCYTES LEAD TO CONTINUOUS EXOGENOUS PROCESSING AND MHC II PRESENTATION

THIS CAUSES RELEASE OF IFN-GAMMA AND TNF-ALPHA WHICH FURTHER ACTIVATES INFECTED MICROPHAGES, RESULTING IN TH1 --> MACROPHAGE --> TH1 LOOP.

REGULATORY T CELL CAPABLE OF MODULATING CYTOKINE LEVELS AND PREVENTING EXCESSIVE INFLAMMATION

IDENTIFIED BY HIGH EXPRESSION OF IL-2 RECEPTOR CD25 AND TRANSCRIPTIONAL ACTIVATOR foxP3 WHICH HELPS PRODUCE INFLAMMATION-SUPPRESSIVE CYTOKINES

HOW B CELLS COMMUNICATE WITH T CELLS

B CELLS BIND EXOGENOUS ANTIGEN TO SURFACE RECEPTOR, WHICH IS THEN INTERNALIZED

ANTIGEN IS PROCESSED VIA ACIDIFIED ENDOSOES AND FRAGMENTS CHANNELED INTO EXOGENOUS PROCESSING PATHWAY (MHC II PRESENTATION)

TH2 CELLS ARE ACTIVATED, GIVING CO-STIMULATORY SIGNALS BACK TO B CELLS (CD40/CD40L)

PROGENITORS OF THE OTHER EFFECTOR CD4+ T CELLS. CAN PRODUCE IL-2 THAT HELPS DRIVE THEIR OWN EXPANSION VIA AN AUTOCRINE STIMULATION

APPEAR TO BE REGULATED BY CELLS OF THE INNATE IMMUNE SYSTEM (APCs DETERMINE WHICH CYTOKINES ULTIMATELY PRODUCED)

COMPOSITE CYTOKINE ENVIRONMENT WILL DETERMINE WHICH T CELL SUBSET WINS, THOUGH OFTEN IT'S A COMBINATION

IFN-GAMMA WHICH COMES FROM NK CELLS ACTIVATED BY IL-2 PRODUCED BY DENDRITIC CELLS AND MACROPHAGES.

NEW TH1 CELLS ALSO PRODUCE IFN-GAMMA WHICH HELPS INHIBIT TH2 CELLS

IL-4 IN ENVIRONMENT OF LOW IFN-GAMMA STARTS INITIAL CONVERSION TO TH2 CELLS

NEW TH2 CELLS PRODUCE MORE IL-4 THUS MAKING MORE TH2 CELLS

TGF-BETA AND IL-10 MADE BY TH2 CELLS INHIBIT PROLIFERATION OF TH1 CELLS

IL-6 PLUS TGF-BETA IN LOW ENVIRONMENTAL IFN-GAMMA AND IL-4

DENDRITIC-CELL-DERIVED IL-23 EXPANDS TH17 DIFFERENTIATION BUT CAN ALSO RELEASE IL-12 THAT INHIBIT

DENDRITIC CELLS DETERMINE IF TH1 OR TH17 CELLS ARE MADE

EXPRESS GAMMA-DELTA CHAINS ON RECEPTORS INSTEAD OF ALPHA-BETA

LOCATED PRIMARILY IN SKIN AND MUCOSAL LAYERS

PROVIDE EARLY ADAPTIVE IMMUNITY, PARTICULARLY BY PRODUCING IMPORTANT CYTOKINES

RECOGNIZES SPECIALIZED NON-POLYMORPHIC SURFACE MOLECULE CD1 INSTEAD OF MHC I OR II

CD1 RESEMBLES MHC I ALTHOUGH IR PRESENTS LIKE MHC II VIA THE EXOGENOUS PATHWAY

CD1 SPECIALIZES IN PRESENTING GLYCOLIPIDS AND PHOSPHOLIPIDS COMMON TO THE MEMBRANES OF MANY BACTERIAL PATHOGENS