Immunology II PDF

Immunology II  Overview of Body Defenses Non-Specific Resistance Specific Resistance (Innate Immunity) (Adaptive Immunity) 1st Line 2nd Line 3rd Line Specialized lymphocytes: 1. Skin...

Immunology II  Overview of Body Defenses Non-Specific Resistance Specific Resistance (Innate Immunity) (Adaptive Immunity) 1st Line 2nd Line 3rd Line Specialized lymphocytes: 1. Skin 1. Phagocytes 1. T cells 2. Mucous 2. Inflammation (Helper & Killer cells) membranes and and fever secretions 2. B cells (Antibodies) 3. Antimicrobial 3. Normal Flora substances 4. Antimicrobial 4. Extracellular substances Killing  Adaptive Immunity = Third line of defense SPECIFIC immunity adaptive, acquired takes time to develop (~5-7 days) mediated by specialized lymphocytes B & T lymphocytes – B cells: Ab-production factories – TC cells: cell mediated immunity (killers) – TH cells: helpers Why does adaptive immunity take so long? T X T T T T T T T T T T T T T T Requires time to grow enough specific T cells to clear the viral infection Billions more T cells each specific for a different pathogen  Fundamental Properties of Acquired Immunity 1. Subject to LEARNING – Learns to distinguish between self and foreign 2. Exhibits SPECIFICITY – Can recognize very tiny regions (1-2 aa differences) of pathogen 3. Exhibits DIVERSITY – Must have broad range of specificities; many pathogens exist ~100,000,000,000 (1011) different Ab specificities! ~10,000,000,000,000 (1013) different T cell specificities! 4. Capable of MEMORY – “Remembers” Ag for future encounters  2 Branches of Adaptive Immune Response: Ags: Ab response: 1. Antibody 2. Cell-mediated Cell Mediated against Response Response response: extracellular against Ags (toxins, intracellular bacteria, Ag & altered free virus) self-cells T-helpers (Virus, required for tumors) Ab response CTL directly kill altered self cells T-helpers required for CTL response  B Cell & Ab Facts activation + antigen antibody-secreting antigen B cell plasma cell clearance each B cell can ONLY make one specificity of Ab another name for Ab is Immunoglobulin(Ig) Abs can be found: – stuck to the surface of a B cell (B cell receptor: BCR) – secreted – circulating in the blood & lymph or patrolling mucosal surfaces Two Main Functions of Abs are Structurally Separated 1. Bind specifically to pathogens variable region: Ag binding sites 2. Recruit other cells to destroy the pathogen constant region (Fc region): binds receptors on immune cells minimal variability  Abs bind to a specific site on the surface of a pathogen a single pathogen may Antibody A contain numerous epitopes Epitopes – EPITOPE = the portion of an Ag that is bound binding antigens on by an Ab regions bacterial cell wall different Abs can recognize different epitopes on the same pathogen Bacterial Cell Antibody B Abs usually recognize external epitopes on pathogens B cell Receptor Maturation & Clonal Selection of B cells Maturation & Clonal Selection of B cells “naïve” B cells B cell encounters and recognizes specific Ag These are all CLONES of the original B cell all have IDENTICAL Ag specificity  Memory Memory B cells facilitate quick response to “familiar” antigens Work upon re-infection  Biological Activities of Abs Opsonization – “prepare to eat” – coating antigen with Ab can enhance phagocytosis Activation of Complement – Ab binding to bacteria can act as the activating step for the complement system – leads to: lysis of the bacterial cell opsonization inflammation  Biological Activities of Abs Ab dependent cellular cytotoxicity = ADCC Some WBC have receptors that can bind to the constant region of Abs (Fc Receptors)  Biological Activities of Abs Neutralization: – Abs can bind surface of pathogen to block adhesion – if the pathogen can’t adhere, it can’t get in – Abs can bind toxins to block their activity Agglutination – Recall Abs have >1 binding site – Abs can “clump” antigens together  5 Ab Isotypes IgM: 1st Ab produced in 1o Ag IgD: membrane-bound Ig on response mature B cells (along with IgM) – membrane-bound form = – biological function unknown surface BCR – pentameric form = serum IgM bind many Ag at the same time IgE: mediates hypersensitivity – highly efficient; good at reactions (hay fever, asthma, activating complement hives, anaphylactic shock) – J chain  facilitates secretion – binds Fc receptors on mast to mucosa cells and basophils IgG: capable of crossing placenta; IgA: predominant Ab in external important in protection of fetus secretions such as breast milk, – complement activation saliva, tears, mucous – bind Fc receptors on – prevents attachment of phagocytic cells (opsonization) pathogens to mucosa – inhibits colonization – protects newborn during 1st month  T Lymphocytes (T Cells) Produced in bone marrow; mature in the thymus Circulate in the lymph and blood and migrate to the lymph nodes, spleen, and Peyer’s patches Antigen-binding sites are complementary to epitopes Have highly specific T cell receptors (TCRs) on plasma membrane – TCRs do not recognize epitopes directly, but only epitopes associated with a MHC protein – Act primarily against body cells that harbor intracellular pathogens  T Cells T cells respond to specific pathogens Kinds of T cells: – Helper T cell (TH cell): send signals to activate other parts of immune response – Cytotoxic T cell (TC cell; CTL): directly kill altered-self cells virally-infected cells (intracellular pathogens), tumors – Regulatory T cells (TR cell): repress adaptive immune responses T cells recognize Ag through TCR TCR only recognizes Ag bound by MHC (compare: B cells recognize free extracellular Ag) MHC = Major Histocompatibility Complex SELF marker on surface of cells specific to each individual – the only people with the same MHC are identical twins first discovered to have a role in graft rejection MHC is a collection of genes on the short arm of chromosome 6 in humans in humans: MHC = HLA (human leukocyte Ag) MHC Class I: HLA-A, HLA-B, HLA-C MHC Class II: HLA-DM, HLA-DP, HLA-DR  MHC molecules are like highway warning signs Under normal conditions (absence of infection): – MHCI and II present “self-peptides” – T cells know there is no danger When there is an infection, MHC can let the T cells know  MHC present protein breakdown products from inside of the cell: peptides may be self or foreign – self: everything is OK – foreign: may be “danger signal” 2 classes of MHC: 1. MHC I: present on almost all body cells, self marker 2. MHC II: present mainly on macrophages, dendritic cells and B cells – “professional antigen presenting cells” – phagocytic cells 2 kinds of T cells match 2 kinds of MHC TC = CTL = cytotoxic T lymphocyte directly kills infected cells TC = CTL : recognize antigen presented on MHC class I TH = T helper cell important for initiation of adaptive immune response TH = T helper cell: recognize antigen presented on MHC class II  TCR/MHC-peptide Complex Formation There is HUGE genetic variation in both the TCR and the MHC – This contributes to the ability of the immune system to recognize many different antigens Where do the peptides come from? – peptides for MHCI and MHCII are obtained by degradation of proteins in different locations  Ag presented by MHCI or MHCII are processed through different pathways MHCI presentation MHCII presentation (endogenous Ag) (exogenous Ag) MHC class I presents endogenous peptides 1. cell is infected by virus altered self cell 2. viral proteins are made through cellular pathways Viruses use host cell machinery 3. viral proteins are degraded and loaded onto MHC-I in the ER 4. MHC-I with viral peptide is transported to cell surface foreign peptide on MHC-I = intracellular infection 5. Killer T cell (Tc cell) can recognize MHC-I/peptide 6. infected cell is killed  MHC class II presents peptides from extracellular (exogenous) antigens 1. phagocytic cell takes up bacteria or toxin 2. bacteria is inside of phagocytic compartment 3. lysosome fuses with phagosome 4. bacteria is digested 5. peptides from digestion are loaded on MHC-II – foreign peptide on MHC-II indicates APC has encountered & phagocytosed Ag – usually bacteria or toxin 6. MHC-II/peptide is transported to cell surface 7. MHC-II/peptide complex can be recognized by TH cells  Whether an antigenic peptide associates with MHC-I or MHC-II is determined by: 1. Mode of Entry into the Cell – MHC-I: Endogenous Ag produced inside the cell viral proteins – MHC-II: Exogenous Ag picked up by phagocytosis bacteria 2. Site of Processing – MHC-I: processed by proteasome in cytoplasm – MHC-II: processed in phagolysosome  When there is no infection… peptides from normal self proteins are processed and presented on MHCI and MHCII Self-peptides DO NOT activate the immune response – Exception is autoimmunity: immune response against “auto” = self discussed in chapter 18 of your textbook  T cell activation results in response that is appropriate to Ag encountered TCR/MHC-I recognition results in DEATH of infected self cell foreign peptide on MHC I indicates an intracellular infection – usually viral – may also be a tumor cell since the cell being recognized is infected, it is of no benefit to the body and must be destroyed virally infected cell  T cell activation results in response that is appropriate to Ag encountered macrophage B- Cell TCR/MHC-II binding results in APC activation MHC-II binding does not result in direct killing because the APCs are NOT infected – they are just signaling danger – B cells  make Abs – macrophages  become more efficient phagocytes  MHC – Summary of Key Points MHC class I MHC class II Found on almost all cells of Found mainly on “Professional the body Antigen Presenting Cells” Presents intracellular peptides – Dendritic cells, Presents antigen to Killer T Macrophage & B cells cells Presents extracellular peptides MHC I presenting cell is killed Presents Ag to Helper T cells Function is to alert Killer T MHC II presenting cell is cells about the health of the activated presenting cell Function is to alert Helper T Normal self-peptides cells if “dangerous” proteins are = safe, no killing present in the body Foreign or altered-self Normal self-peptides peptides = safe, TH doesn’t help immune = danger, kill me! cells become activated Foreign or altered-self peptides = danger, TH helps immune cells become activated T-helper cells (CD4+) are central to the adaptive immune response  Types of Acquired Immunity Naturally acquired active immunity – individual exposed to Ag in course of daily life – sub-clinical infections can confer immunity Naturally acquired passive immunity – natural transfer of Abs – eg) Maternal transfer of Abs over placenta or thru breast milk Artificially acquired active immunity – Result of vaccination, prepared Ags/vaccines are introduced – Vaccine/Ags are altered so they can’t cause disease, but rather stimulate an immune response Artificially acquired passive immunity – introduction (injection) of preformed Abs from an animal or person who is already immune to the disease Comparison of the types of Acquired Immunity  Cell Death Necrosis: whole cell is destroyed at once – Leads to induction of inflammatory pathway – E.g. bruising Apoptosis: programmed cell death – Prevents release of potentially damaging cellular elements into host tissues – Leads to rapid clearance of killed cell with no inflammation – E.g. the mechanism used by Killer T cells to eliminate altered- self cells (infected or tumor self cells)  Burkitt’s Lymphoma (EBV) In cancer, apoptosis is inhibited and proliferation of cells is unimpeded EBV blocks apoptosis – EBV prevents cell from dying – mechanism of pathogenicity for this and other viruses  Vaccination a way to manipulate the immune response Inject an “image” of the pathogen – small piece of the pathogen – related, killed or weakened pathogen immune system becomes familiar w/ the “picture” of the pathogen Preparations are made to combat the real pathogen in case it is ever encountered vaccination works to prevent disease – the immune system remembers what it has encountered before vaccination provides protection only against the intended disease – the immune response is specific – i.e.: if you get vaccinated against measles, you can still get chickenpox  Vaccines vaccination: deliberate induction of immunity by injecting a non-pathogenic form of a pathogen 6 types: 1. attenuated live vaccine 2. inactivated whole-agent vaccine 3. toxoid 4. subunit vaccine 5. conjugated vaccine 6. nucleic acid vaccine  Attenuated whole-agent vaccine living but weakened microbes, closely mimics actual infection 95% effective often life-long immunity examples: – Sabin (oral) polio vaccine – MMR (measles, mumps, rubella) disadvantage: very slight risk that agent may mutate back to virulent form not suitable for people with compromised immune system Inactivated whole-agent vaccine microbes that have been killed examples: – rabies – Salk (injectable) polio vaccine – Influenza A – pertussis  Subunit vaccines made of only antigenic fragments of a microorganism – must be capable of stimulating immune response produced by genetic engineering – bacteria or yeast produce the protein of interest – “recombinant vaccine” example: Hepatitis B vaccine – yeast cells make an antigenic portion of the protein coat Toxoids vaccine directed against toxin, not the microbe itself effective when toxin is major pathogenicity factor requires boosters for full immunity examples: – diphtheria – tetanus  Conjugated vaccines used for organisms that have polysaccharide capsules (glycocalyx, slime layer) – poor antigenicity children