INFLAMMATION– Components of both the innate and adaptive immune systems may respond to certain

antigens to initiate a process known as inflammation. – When the outer barriers of innate immunity—skin and other epithelial layers—are

damaged, the resulting innate responses to infection or tissue injury can induce a complex cascade of events known as the inflammatory response.

– Inflammation may be acute (short-term effects contributing to combating infection, followed by healing)—for example, in response to local tissue damage—or it may be chronic (long term, not resolved), contributing to conditions such as arthritis, inflammatory bowel disease, cardiovascular disease, and Type 2 diabetes.

– Inflammatory responses are activated by the innate immune response to local infection or tissue damage—in particular, by the pro-inflammatory cytokines and certain chemokines that are produced. Key early components of inflammatory responses are increased vascular permeability, allowing soluble innate mediators to reach the infected or damaged site, and the recruitment of neutrophils and other leukocytes from the blood into the site.

– A later component of inflammatory responses is the acute phase response (APR), induced by certain pro-inflammatory cytokines (IL-1, TNF-α, and IL-6). The APR involves increased synthesis and secretion by the liver of several antimicrobial proteins, including MBL, CRP, and complement components, which activate a variety of processes that contribute to eliminating pathogens.

Hallmarks of localized inflammatory response, induction and contribution to innate immunity– Inflammation is characterized by redness, heat, swelling, pain, and sometimes loss of

local function. – Cytokines made by PRR-activated resident innate cells act on the vascular endothelium,

causing vascular dilation (producing redness and heat) and increasing permeability, resulting in influx of fluid and swelling (producing edema). Prostaglandins generated following the induced expression of COX2, together with mediators such as histamine, lead to the activation of local pain receptors. The swelling and local tissue damage can result in loss of function.

– The increased vascular permeability allows an influx of fluid containing protective substances, including opsonins and complement (as well as antibodies, if present). Local production of chemokines, together with induced expression of adhesion molecules on vascular endothelial cells, recruits to the site additional innate cells, such as neutrophils and macrophages, which contribute further to innate responses and pathogen clearance through phagocytosis and release of antimicrobial mediators. Proinflammatory cytokines made during this innate response may also act systemically, triggering the acute phase response.

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MAJOR HISTOCOMPATIBILTY COMPLEX (HLA Complex)– Major Histocompatibility Complex

• Cluster of genes found in all mammals• Its products play role in discriminating self/non-self• Participant in both humoral and cell-mediated immunity

– MHC Act as antigen presenting structures– In Human MHC is found on chromosome 6

• Referred to as human leukocyte antigen (HLA) complex– In Mice MHC is found on chromosome 17

• Referred to as H-2 complex

– For the purpose of this unit (SBC 403), we shall concentrate on the HLA complex

– Genes of MHC Organized in 3 Classes• Class I MHC genes

– Glycoproteins expressed on all nucleated cells– Major function to present processed antigens to CD8+ TC cells

• Class II MHC genes– Glycoproteins expressed on macrophages, B-cells, dendritic cells

(pAPCs).– Major function to present processed antigens to CD4+TH cells

• Class III MHC genes– Products that include secreted proteins that have immune functions.

Examples: Complement system (C4, Bf, and C2), inflammatory molecules

Class I, II and III MHC– Class I MHC genes found in regions A, B and C in Humans – Class II MHC genes found in regions DR, DP and DQ – Class I and Class II MHC share structural features

– Both involved in APC– Class III MHC have no structural similarity to class I and II

– Examples: TNF, heat shock proteins, complement components

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MHC Genes Are Polymorphic– MHC Products Are Highly Polymorphic

– Vary considerably from person to person– However, Crossover Rate Is Low

– 0.5% crossover rate– Inherited as 2 sets (one from father, one from mother)– Haplotype refers to set from mother or father

– MHC Alleles Are Co-Dominantly Expressed– Both mother and father alleles are expressed

Class I MHC Molecule– Comprised of 2 molecules

– α chain (45 kDa), transmembrane– 2-microglobulin (12 kDa) – Non-covalently associated with each other

– Association of chain and 2 is required for surface expression– chain made up of 3 domains (1, 2 and 3) – 2-microglobulin similar to 3 – 1 and 2 form peptide binding cleft

• Fits peptide of about 8-10 a/a long

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– 3 highly conserved among MHC I molecules• Interacts with CD8 (TC) molecule

Class II MHC Molecule– Comprised of and chains

– chain and chain associate non-covalently– and chains made up of domains

– 1 and 2 ( chain) – 1 and 2 ( chain)

– 1and 1 form antigen binding cleft– and heterodimer has been shown to dimerize– CD4 molecule binds 2/2 domains

Class I and II Specificity

– Several hundred allelic variants have been identified in humans– However, up to 6 MHC I and 12 MHC II molecules are expressed in an individual– Enormous number of peptides needs to be presented using these MHC molecules– To achieve this task MHC molecules are not very specific for peptides (Unlike TCR and

BCR)– Promiscuous binding occurs

– A peptide can bind a number of MHC– An MHC molecule can bind numerous peptides

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Class I and II Diversity and Polymorphism– MHC is one of the most polymorphic complexes known– Alleles can differ up to 20 a/a– Class I alleles in humans: 240 A, 470 B, 110 C– Class II alleles in humans: HLA-DR 350 , 2 !– HLA-DR

– genes vary from 2-9 in different individuals!!!,– 1 gene ( can combine with all products increasing number of APC

molecules)– DP (2 , 2 ) and DQ (2 , 3 )

Antigen processing and presentation– In most cases, class I molecules present processed endogenous antigen to CD8+ TC cells

and class II molecules present processed exogenous antigen to CD4+TH cells.

Class I MHC Peptides– Peptides presented thru MHC I are endogenous proteins– As few as 100 peptide/MHC complex can activate TC

– Peptide features– size 8-10 a/a, preferably 9

– Peptides bind MHC due to presence of specific a/a found at the ends of peptide. Ex. Glycine at position 2

– Endogenous antigens are degraded into peptides within the cytosol by proteasomes, assemble with class I molecules in the RER, and are presented on the membrane to CD8+

TC cells. This is the endogenous processing and presentation pathway.

Class II MHC Peptides– Peptides presented thru MHC II are exogenous

– Processed through exogenous pathway– Peptides are presented to TH

– Peptides are 13-18 a/a long– Binding is due to central 13 a/a– Longer peptides can still bind MHC II

– Like a long hot dog– MHC I peptides fit exactly, not the case with MHC II peptides

– Exogenous antigens are internalized and degraded within the acidic endocytic compartments and subsequently combine with class II molecules for presentation to CD4+ TH cells. This is the exogenous processing and presentation pathway.

– Peptide binding to class II molecules involves replacing a fragment of invariant chain in the binding groove by a process catalyzed by nonclassical MHC molecule HLA-DM.

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– In some cases, exogenous antigens in certain cell types (mainly DCs) can gain access to class I presentation pathways in a process called cross-presentation.

– Presentation of nonpeptide (lipid and lipid-linked) antigens derived from pathogens involves the nonclassical class I–like CD1 molecules.

MHC Expression– Expression is regulated by many cytokines

• IFN, IFN, IFN and TNF increase MHC expression– Transcription factors that increase MHC gene expression

• CIITA (Transactivator), RFX (Transactivator)– Some viruses decrease MHC expression

• CMV, HBV, Ad12– Reduction of MHC may allow for immune system evasion

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