Principles of Adaptive Immunity

Principles of Adaptive Immunity Chapter 3 Parham Hans de Haard 17 th of May 2010

Agenda Recognition molecules of adaptive immune system Features adaptive immune system Immunoglobulins and T-cell receptors Generation of Immunoglobulins and T-cell receptors Gene rearrangement Clonal selection Antigen presentation by MHC Presentation by dendritic cells MHC class I for elimination of intracellular pathogens MHC II for elimination extracellular pathogens Antibodies Antibody mediated clearance Somatic maturation and class switching to improve clearance Autoimmune diseases and transplant rejection

Adaptive Immunity Innate immune response: fixed repertoire of receptors and soluble factors recognizing general type of molecules inherited from one generation to next Adaptive immune response: infinite number of (B and T cell) receptors and soluble molecules expressed by lymphocytes strong response precisely targeted against a particular pathogen on the basis of small differences distinguishing one pathogen from the other not inherited, every individual makes its own subset of molecules

B and T cell receptors B cell receptors (or immunoglobulins) and T cell receptors have variable region recognizing the pathogen and constant region Molecule of pathogen recognized by B / T cell receptor is called antigen Specific recognition, i.e. no binding to related structures of other pathogens Plasma cells are B cells secreting soluble form of immunoglobulin called antibody B cell receptors have two identical heavy chains associated with two identical light chains; T cell receptors have α and β chain

Diversity generated by gene rearrangement Variable regions immunoglobulins (Ig) and T cell receptors (TCR) encoded by separate V, (D) and J segments Ig heavy chain and TCR β chain contain additional D segment, Ig light chain and TCR α only V and J Rearrangement of genomic DNA leads to fusion of one V, one D and one J segment placed in juxtaposition to C region Diversity generated by: fusion of V, D and J introduction nucleotides in joints between segments Combination of heavy & light / α & β chains

Clonal selection Humane immune system makes millions of different Igs / TCRs, each produced by an individual lymphocyte (i.e. clone) Combination uniformity at level of individual lymphocyte and diversity at level of population of lymphocytes allows tailored made response against one type of pathogen Population of naive B & T cells checked for recognition of pathogen specific antigens Only reactive clones will proliferate and differentiate into effector cells: clonal selection

Dendritic cells present antigen to naïve T and B cells Dendritic cells (DCs) type of phagocytic leukocyte specialized in uptake and breakdown of infectious agents Become mobile upon infection and transport pathogen via lymph to secondary lymphoid tissue Antigen loaded DCs present and activate naive T cells recognizing pathogen specific antigens (clonal selection) Matured T cells will activate naive B cells to produce pathogen specific Igs / Abs

Dendritic cells present linear peptides to T cells via MHC DCs take up pathogen an degrade pathogen derived proteins into small linear peptides with their own proteases or those from other cells Peptides bind to Major Histocompatibility Complex (MHC) and are transported to cell membrane Appropriate TCR of T cell binds leading to proliferation and differentiation of T cell clone

Interaction MHC peptide complex with TCR / CD4 or CD8 MHC less specific binding to peptides, only determined by length and presence of certain residues on fixed positions Each MHC encoded by single gene, large diversity in human population due to many different genetic variants (alleles) Diversity increased by heterozygous presence of MHC genes CD4 and CD8 function as co-receptor and interact with MHC II and MHC I, respectively

MHC class I presents antigens from intracellular pathogens Intracellular infection (f.i. virus) leads to replication and synthesis of pathogen s proteins using host s machinery (initially in DCs) Pathogen s proteins degraded in cytosol and transported to ER Interaction with MHC I and transport complex via Golgi to plasma membrane Display of MHC I peptide complex to naive CD8 + T cells in secondary lymphoid tissue leading to generation of cytotoxic T cells T cyt circulate and kill infected cells everywhere in body All cells can express MHC class I

MHC class II presents antigens from extracellular pathogens A B Proteins from pathogens bound by receptors on macrophage or B cells, internalized via and degraded in endocytic vesicles Interaction MHC II with peptides in vesicles, subsequent transport to cell membrane Interaction MHC II peptide complex with helper T cells results in generation of T H which: (A) attract and activate neutrophils / monocytes and derived macrophages => killing pathogens (B) activate B cells for producing pathogen specific Abs Only B cells and macrophage express MHC class II

Elimination extracellular pathogens by antibodies Antibodies present in blood, lymph and intracellular fluid connective tissues => bind to pathogens in infected tissues everywhere in the body Antibodies can neutralize by preventing binding of pathogen to cellular receptor or interfere in its replication Opsonization is process of targeting phagocytic cells to pathogen for ingestion and destruction Fc of antibody induces opsonization via binding to Fc receptors on phagocytes Combination of IgG and complement induces greatest stimulation phagocytosis

Affinity maturation and class switching improves efficacy antibody During B cell development random mutations introduced in rearranged VH and VL Only B cells expressing better binding antibody (i.e. higher affinity) will proliferate Several heavy chain isotypes exist differing in constant region and in efficacy of inducing clearance of pathogen (i.e. effector function) IgM is first produced: => large, low affinity, poor effector function Isotype switch: fusion VH to other isotype like IgG IgG => smaller (better tissue penetration), improved affinity, better effector functions

Clonal selection avoids anti-self and drives response to pathogens Immature T cells positively selected for binding of TCR to MHC (in cortex thymus) Next round of negative selection for T cells binding too strongly to MHC (in medulla of thymus) => TCR should have good affinity for MHC peptide complex Since MHC class I expressed on all cells self reactivity has to be eliminated => T cell repertoire is self-tolerant B cell development dependent on T H => removal of anti-self T H avoids generation autoimmune Abs During B cell development also negative selection for anti-self Abs (bone marrow)

Autoimmune diseases Adaptive immunity is highly regulated process leading to tailormade response against pathogens, which passed barrier of innate immune system Misdirected responses lead to serious diseases: allergy caused by strong response against harmless substance (allergens like grass pollens, foods or house dust) => IgE responsible isotype, interaction of IgE on mast cells with allergen insulin-dependent diabetes caused by autommune Abs against insulin-secreting β cells of islets of Langerhans in pancreas other examples of autoimmune diseases: rheumatoid arthritis and multiple sclerose caused by antibodies against pathogens with cross-reactivity against self Ags

Transplant rejection Transplant rejection caused by differences in MHC (tissue incompatibilities) Underlying problems: large diversity in MHC genes: > 1000 variants in humans, each individual has <20 types clonal selection only checks for anti-self against own MHC types => high probability of reactivity against donor MHC MHC compatible donors found within families transplantation organ from non-related donor frequently leads to strong rejection reactions => treatment with drugs suppressing adaptive immune system with sideeffect increased sensitivity to infections and cancer

Principles of Adaptive Immunity Chapter 3 Parham Hans de Haard 17 th of May 2010