An Overview of Immune System

1. An Overview of Immune System Swapan K. Ghosh Professor of Immunology

2. BASIC TENETS OF VERTEBRATE IMMUNE SYSTEM • Sophisticated Innate or non-specific immune apparatus • Sophistication due to ability to serve as a liaison between Innate & Adaptive immunity • Molecular pillar: complements, cytokines • Super-sophisticated Acquired or specific immune Apparatus • Unique ability to specifically recognize extra- & Intracellular antigens (non-self Mol.) • Exhibits D S M T S • Molecular pillars: Ig, TCR, MHC, cytokines

3. Three aspects of immune activation • For specific adaptive immunity: Clonal selection theory: to explain - selection of specific B and T lymphocytes (Burnet’s hypothesis): P L E A S E • For innate immunity: leads to expression of TOLL receptors & then co-stimulatory molecules • Infectious Non-Self theory (Janeway) to stimulate co-stimulatory molecules against pathogens • Danger Model (Madzinger) to stimulate against any stressful exposure

4. Innate immunity’s Pattern Recognition Receptors (PRR) • Reflections on self : immunity and beyond in Science Vol.296 12 April 2002 SNS=self-nonself structure

5. Infectious Non-self model • Infectious nonself (INS), by Janeway : APCs have their own form of self/nonself discrimination : they do not co-stimulate unless activated via PRRs (receptors for evolutionarily distant infectious non-self, i.e. the immune system has a phylogenetic memory of infectious organisms). The universe of antigens is split into 2 sets : noninfectious self (set a) and infectious nonself (set f). It tends to ignore noninfectious nonself (set b - f).

6. Limitations of INS model • It does not explain why viruses that do not generate dsRNA stimulate immunity, why transplants are rejected, what induces autoimmunity, why tumors are sometimes spontaneously rejected, or how nonbacterial adjuvants, such as alum, work.

7. Danger model • APCs are activated by endogenous cellular alarm signals from distressed or injured cells. The universe of antigens is split into 2 sets : - Those associated with dangerous entities or harmless ones, defining as dangerous anything that induces stress or nonphysiological (lytic) cell death. Dangerous entities may be self (set c) such as mutations that lead to stress or inappropriate cell death or inefficient scavenging; or -Nonself, such as pathogens (set e), environmental toxins (set d), and such. Set f would contain fetuses and evolutionarily distant organisms that have PAMPs, but that are not dangerous (e.g. symbiotic organisms, well-adapted viruses).

8. PAMP recognition Receptors • Toll-like receptors (TLRs) are Type 1 transmembrane proteins with an extracellular LEU-RICH REPEAT (LLR) and an intracellular TOLL/IL1 RECEPTOR (TIR) domain. The originally discovered TOLL receptor in Drosophila Melanogaster was considered a maternal-effect gene controlling dorsoventral axis formation in embryo

9. Different TOLL Receptors • TLR1 (expressed constitutively on many cell types) binds to ? • TLR2 (highly expressed in APCs (monocytes, DCs, ..) and endothelial cells • TLR3 (expressed on DCs) binds to dsRNA and its synthetic analogue polyinosine-polycytidylic acid (poly(I:C)). • TLR4 (highly expressed in monocytes; weakly expressed in neutrophils and basophils)

10. TOLL R continued • TLR5 (highly expressed in monocytes and on the basolateral side of intestinal epithelium; weakly expressed in neutrophils and basophils) binds to flagelin FliC protein. • TLR6(expressed constitutively on many cell types) binds to ? • TLR7 (expressed in B cells and PDCs) binds to imidazoquinoline immunostimulants. No natural ligand is known. • TLR8 binds to ? • TLR9 (highly expressed in B cells and PDCs; weakly expressed in monocytes, NK cells and T cells) binds to unmethylated R1pR2CpGpY1pY2 DNA sequences (where R1 is a purine with preference for G, R2 is a purine or T, and Y1 and Y2 are pyrimidines). • TLR10 (higly expressed in B cells)

11. Innate Vs. Adaptive • APCs cannot distinguish self from non-self • They capture normal tissue antigens as well as non self-antigens and present both to passing T cells • In self-nonself models, T cells must be trained to tell the difference between these foreign and self antigens. Thymus does it. • Both APC & B, T cells undergo recognition, activation and execution phases.

12. Activation of APC • Triggering TLRs on specialized APCs induces the expression of costimulatory molecules on the cell surface, which is necessary for the activation of naive T cells specific for antigenic peptides expressed on the same APC in complex with MHC molecules. • Because the costimulators are induced by PAMPs, their expression on APCs flags the antigenic peptides presented by the same APC as being of microbial origin and activates antigen-specific T cells. • Self-peptides expressed and presented by these APCs are not recognized as nonself, because T cells specific for these peptides are eliminated during negative selection in the thymus. Thus negative selection and microbial induction of costimulatory molecules together ensure that the adaptive immune response is generated against infecting pathogens but not against self-antigens • TLR-mediated recognition is vital for the generation of TH1, but not TH2 effector responses.

13. Dawning of Adaptive immunity • Adaptive or acquired or specific immune system, together with lymphoid tissue (a particular kind of connective tissue), appeared abruptly among Vertebrata at some point in the divergence of the class Chondrichthyes (cartilaginous fishes) from Hyperoartia (cyclostomes), where it is completely absent. Members of the subclass Elastobranchii (elasmobranchs) are the oldest organisms with Ig-like genes. • The evolution of adaptive immunity appears to have been made possible by the invasion of a putative immunoglobulin-like gene by a retrotransposon encoding a gene able to catalyze gene rearrangement (eg, RAGs)

14. APC & T-lymphocytes • In an immune system poised for danger, the T cells need only to distinguish APCs from everything else • Resting T cells need 2 signals to be activated; signal A from TCR binding to MHC/peptide and signal B (co-stimulation) from an APC. It states that T cells die if they receive signal A without signal B (leading to tolerance) and become activated if they receive both. • Resting T cells can receive signal B only from APCs. Interdigitating DCs (and, perhaps, macrophages) can serve as APCs for both virgin and experienced T cells, and B cells can re-stimulate experienced but not virgin T cells.

23. T-cells • Thymus educated involving MHC class 1 and class II molecules • CD4+ T-cells: MHC class II-mediated: Th1 (CMI) & Th2 (Humoral)– cytokine difference • CTL: CD8+ T cells: Killer • Aberrant lymphocytes: non-thymus educated NK cells • MHC CD1allele presents non-protein Ag to T cells

24. B-lymphocytes & T cells • B-cells see native antigen, produce IgM • Memory B-cells require T-help; produce IgG, IgA, IgE; APCs play little role • Igs are antibodies secreted by PC as well as receptors on B-cells • Naïve B-cells express two Ig receptors: IgM, IgD • Memory B-cells express one Ig receptor, IgG, IgA, IgE

28. B-cell characteristics • B-lymphocytes: B1 and B2 cells: humoral response • B1:in peritoneum and cavities. not recirculating, they are absent from lymph nodes, spleen and peripheral blood. Not much hypermutable. Lack interaction with T cells • B-2 cell (conventional B cell) • BCR consists Ig (for Ag recognition) plus Ig & Ig (for signal transduction); Ig has premonition of what Ag to recognize at the germ line

29. X-Ray Crystallograph of Ig

31. Ig Domains

35. Ig Gene rearrangement in a B-cell