The genetic basis of immune and autoimmune responsesGF Bottazzo, M Locatelli, A Fierabracci and D FruciScientific Directorate, Autoimmunity and Immunogenetics Laboratories, Ospedale Pediatrico Bambino Gesu`, Scientific Institute (IRCCS),Rome, Italy
Bottazzo GF, Locatelli M, Fierabracci A, Fruci D. The genetic basis of immune and autoimmuneresponses. Acta Pdiatr 2004; Suppl 445: 3842. Stockholm. ISSN 0803-5326HLA class I and class II molecules play a major role in the presentation of short, pathogen-derivedpeptides to T cells, a process that initiates the adaptive cellular and humoral immune responses.However, the factors governing a cells ability to respond or not to particular peptides are still notcompletely understood. Taking the example of a viral infection, in tissues infected with a virus,viral particles are taken up by antigen-presenting cells and uncoated. The viral DNA or RNAenters the nucleus, where it replicates. mRNA enters the cytosol and is transcribed into proteins.These proteins are degraded in proteasomes and the resulting peptides (810 residues) are loadedonto class I molecules for export to the surface of the cells. In the meantime, the groove of theclass II molecules is also preparing to accommodate peptides (1224 residues) generated by theendocytic protein-processing pathway. The surface of the infected cell then becomes adorned withpeptide-loaded human leukocyte antigen (HLA) molecules. CD4 T helper lymphocytes engageclass II molecules and elicit responses from B cells, which will ultimately lead to antibodyproduction, whereas CD8 T lymphocytes become cytotoxic T cells. As a consequence, the virusis eliminated from the body. However, certain mysteries and challenges remain. How can, as anexception to this rule, an autoimmune response be the escape from the perfect machinery? Thisreview offers some hypotheses on how to see the problem through to its solution.Key words: Autoimmunity, HLA class I and II pathways, self-toleranceGF Bottazzo, Direzione Scientifica, Ospedale Pediatrico Bambino Gesu`, (IRCCS), PiazzaSantOnofrio 4, I-00165 Rome, Italy (Tel. 39 06 6859 2127, fax. 39 06 6859 2101, email@example.com)
Throughout evolution, the immune system has devel-oped a sophisticated mechanism, which protects theindividual against intracellular and extracellular patho-gens, such as viruses and bacteria. Once the pathogenhas entered the body, the immune system is confrontedby a series of challenges. First in line are the innate (ornatural) responses of infected cells, followed by theresponse of cellular elements and adaptive (or acquired)immunity, in which B and T cells detect foreignantigens by means of their receptors. This providesflexible protection against the antigenic universe ofviruses, bacteria, parasites, etc. Each B and T cell has itsown antigen receptor and, upon antigen recognition,undergoes clonal expansion to form effector andmemory cells, thus providing specific acquired immu-nity. The B cells bind native antigens through immuno-globulins (Ig) expressed on their surface; uponmaturation, the B cells will be converted into plasmacells, which secrete antibodies. Through their T cellreceptors (TCRs), cytotoxic and helper T lymphocytesrecognize small antigenic peptide fragments in associa-tion with molecules of the major histocompatibilitycomplex (MHC). The MHC gene complex encodes twomajor classes of peptide receptors, human leukocyteantigen (HLA) class I and class II molecules (1). HLA
class I molecules are expressed on virtually allnucleated cells and are essential to detect pathogensthat replicate intracellularly, such as viruses. CD8cytotoxic T lymphocytes (CTLs) screen cell surfaces forHLA class I-bound peptides. HLA class II moleculesare expressed only on the surface of professionalantigen-presenting cells (APCs), such as macrophages,monocytes, dendritic cells (DCs), B cells, Langerhanscells, activated T cells and epithelial cells in the thymus,and present exogenously derived proteins to CD4 Thelper (Th) cells. Differences in assembly, intracellulartransport and cooperation with specialized chaperonsallow HLA class I and class II molecules to presentpeptides coming from distinct intracellular compart-ments, and therefore from different sources. However,there are exceptions, and class I may handle exogenousantigens and class II may present endogenous peptidesnot coming from endosomes (see below).
Although T cells respond to antigens with highspecificity, they are not able to drive their response inthe absence of professional APCs. In fact, it is necessaryto distinguish between the affector and the effectorphases of T cell triggering. In the affector phase, CTLsencounter antigen for the first time. Activation of suchnaive T cells requires the interaction of HLApeptide
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and co-stimulatory molecules expressed on the surfaceof a specialized APC, most likely DCs and macro-phages. Immature DCs are considered immunologicalsensors, alert for potentially dangerous microbesthroughout the body. DCs capture the microbe or itsproducts by several mechanisms and leave the site ofinfection migrating towards the T cell areas of theproximal lymph nodes, via the afferent lymphaticsystem. During their migration, DCs undergo a matura-tion process, where they up-regulate their T cell co-stimulatory functions, becoming efficient activators ofnaive T cells. This occurs presenting both HLA peptidecomplexes and additional co-stimulatory signals, i.e.molecules of the B7 family, to T cells (2). The inter-action between these co-stimulatory signals and theircorresponding ligands on T cells results in the up-regulation of other ligands and secretion of variouscytokines that play different roles in the immuneresponse. Once activated by their encounter with anantigen, naive T cells proliferate, differentiate andacquire the capacity to enter peripheral tissues and tofight the invading pathogen, the so-called effectorphase.
While it is easy to figure out how DCs can captureexogenous pathogen products and present them to HLAclass II-restricted Th cells, this is more complicated forHLA class I-restricted responses, generally thought totarget endogenous antigens. However, another physio-logical pathway does exist, termed cross-presentation.For a long time, this was considered to be just amarginal phenomenon, but it has now been recognizedas playing an essential role in priming CTL responses toviruses. Indeed, cross-presentation refers to any situa-tion in which antigens synthesized in one cell can becaptured as exogenous antigens by APCs, processed inthe HLA class I antigen-presentation pathway and usedto prime CTLs (3).
HLA class I pathwayCells constitutively display peptides derived from allproteins, self-normal, non-self (e.g. viruses) or mutant(e.g. tumors), since they are not able to distinguishbetween them. It is essential that HLA class I moleculesdisplay the largest possible repertoire of peptides. It hasbeen estimated that approximately one third of newlysynthesized proteins are degraded within minutes ofbeing synthesized, thus representing the major source ofpeptides for HLA class I molecules.
How does this occur? First, a protein is covalentlylabeled by linkage to the ubiquitin molecules andsubsequently fed into the cells mincerthe protea-someto be degraded into peptides of up to 15 aminoacids. Over 70% of generated peptides are too small tobind HLA molecules and are thus rapidly hydrolyzed tosingle amino acids recycled for the general metabolismof the cells. The ubiquitinproteasome system is the
major mechanism used by eukaryotic cells to degrademisfolded and damaged proteins at the end of their life.Two types of proteasome have been described: theconstitutive (or standard) proteasome and the immuno-proteasome. The first can be expressed in any cell type,while the immunoproteasome (generated as a conse-quence of interferon-) is expressed exclusively in cellsof the lymphoid tissue, such as thymocytes, splenocytesand DCs. Peptides generated by these two types ofproteasome seem to be different, but their exact role hasyet to be fully elucidated.
Once generated, these peptides enter the endoplasmicreticulum (ER) via TAP proteins and, after interactionwith novel aminopeptidases, they are appropriatelytrimmed to 810 amino acids to fit one of the emptygrooves of HLA class I molecules. Bound peptidestabilizes the HLA class I molecule, which can beefficiently transported to the cell surface. Since onlyHLA class I molecules loaded with peptides are stable,the spectrum of class I-presented peptides accuratelyreflects the proteins expressed within a cell (6). In thisway, the CTLs continuously sample a large number ofpeptides in both healthy and infected cells. Theinhibition of any component of this pathway substan-tially decreases HLA class I expression on the cellsurface.
In humans, the three different HLA class I molecules(-A, -B and -C) are characterized by an elevatedpolymorphism (up to 800 different alleles). Each ofthese molecules is coded by alleles derived frompaternal and maternal chromosomes, which means thateach individual can express up to six different HLAclass I molecules. If one considers that each allele canbind a unique set of peptides, a single cell will simul-taneously express a large number of HLA class Imolecules each with a different set of peptides, thusproviding the basis for efficient immune surveillance byCTLs. The function of an HLA class I molecule isinextricably related to its structure. The peptide bindinggroove contains six pockets, AF, that accommodatepeptide side-chains of the anchor residues. Thesepockets vary between allelic variants and thus deter-mine the set of peptides that can be bound to each HLAclass I groove.
HLA class II pathwayUnlike HLA class I molecules, HLA class II molecules(DR, DQ and DP)