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198 Cards in this Set
- Front
- Back
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NK Cell
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A large granular lymphocyte that kills virus-infected cells
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Neutrophil
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The predominant type of granulocyte in blood, also found at sites of acute inflammation
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B lymphocyte
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A cell that can be stimulated by antigen to differentiate into an antibody-secreting plasma cell
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Eosinophil
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A granulocyte involved in killing some parasite, and in atopic allergic reactions such as asthma. containing basic and cationic proteins, can kill heminths by an extracellular mechanism.
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T lymphocyte
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A cell that matures in the thymus and recognises peptide antigen bound to MHC molecules on antigen-presenting cells
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Mast Cell
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A cell found in mucosal and connective tissues, with granules containing histamine
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Monocyte
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A blood cell that can mature into a macrophage
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Basophil
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A granulocyte found in relatively low numbers in normal blood, with granules that stain with basic dyes and contain histamine
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IgE
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Found in extremely low concentrations in human blood; binds to mast cells and is important in allergic reactions such as hay fever
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IgM
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Found in blood as a pentamer; the main antibody produced in a primary immune response. Best at complement activation.
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IgA
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Protects mucosal surfaces, where it is found as a dimer with J chain and secretory component. Also found in breast milk.
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IgD
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Found in low concentrations in blood, but present as a receptor on many B cells
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IgG
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The predominant class of antibody in blood, associated with secondary responses to antigens. Only class that can pass through placenta, giving protection to fetus. IgG1, IgG2, IgG3 and IgG4, 4 subclasses. Most abundant.
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C3
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Cleavage of this molecule occurs when a convertase is produced in response to microbes or immune complexes
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MHC class II
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These molecules are present on APCs and present antigen to helper T cells
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CD3
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Present on all T cells and involved in activation of these cells in response to antigen
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Cytokines
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A group of molecules with diverse functions in the immune system; includes interleukins, interferons etc
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MHC Class I
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Present on all nucleated cells; presents antigen to cytotoxic T cells
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CD4
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Present on helper T cells; a receptor for HIV
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Chemokines
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Low molecular weight cytokines that stimulate the migration of particular cell types
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CD8
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Found on cytotoxic T cells but not helper T cells
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Viral replication cycle
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1. Attachment to host cell
2. Un-coating of virus 3. Control of DNA, RNA and/or protein production 4. Production of viral subunits using cell machinery 5. Assembly of virions 6. Release of virions – budding process as cell is lysed |
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Anti-viral specific targets
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-difficult to achieve distributional selectivity
-interfere with viral nucleic acid synthesis or regulation, viral cell binding, interrupting virus un-coating, or stimulating host cell immune system |
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Ideal drug should not be:
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-toxic, carcinogenic, allergenic, mutagenic, teratogenic
-however antiviral drugs must penetrate host cells to be effective, therefore high toxicity |
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In vitro susceptibility testing
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-use of cell cultures incubated with virus and drug of choice
-determines relative antiviral activity and drug resistance development |
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Ideal drug should be:
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-water soluble
-stable in blood stream -easily taken up by cells -many antivirals are effective in vitro, but ineffective in vivo |
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Considerations in antiviral therapy
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-requirement for competent host immune system (can't be immunosuppressed)
-supportive and prolonged suppressive therapy |
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Viral Latency
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Latency: recurrence of infection
4 types: acute, persistent, latent reactivating, slow reasons: - infection in non replicating cells, joint replication processes (competition in replication rates in host vs. virus), limited immune detection (virus lowers normal antigenic detection process) -no antiviral agent eliminates viral latency |
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virustatic agents
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-will inhibit virus but not kill it, most antiviral drugs are virustatic agents
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Antiviral Resistence
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-huge problem for antiviral drugs
-viruses have small genomes, giving them rapid replication rates, high spontaneous mutation rate is very high -mutations prevent binding of drug to active sites of key enzymes such as proteases and reverse transcriptases |
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Herpes virus
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-one of the most common DNA viruses, globally biggest hitter
-simplex: cold sores -varicella zoster: chicken pox -Epstein Barr: glandular fever symptoms: flu-like and blister/ulcer stage -infects sensory ganglia where it becomes latent |
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-Aciclovir
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-against herpes virus
-first antiviral developed -high theraputic index: concentration to cause theraputic effect is lower than concentration that causes toxicity -requires intracellular phosphorylation to be active |
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Aciclovir tri-phosphate
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-DNA chain terminator
-integrates in virus genome, inhibits viral DNA polymerase -host is not susceptible to its effects, giving it minimal toxicity |
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Mechanism of action of HIV
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-targets CD4 cells, progressive loss of CD4 is defining HIV characteristic
-DNA virus becomes integrated in host genome and releases virions in virus |
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GP41 and GP120
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transmembrane glycoproteins, important in HIV penetrating membrane of host cell
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Enfurvitide
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-fusion inhibitor
-antiviral, prevents utilization of GP41 from combining HIV virus with host cell -binding to GP41, preventing HIV from interacting with CD4 cell -emergence of resistence bc of mutation in gp41 |
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Maraviroc
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-CCR5 extracellular inhibitor
-antiviral -binding to CCR5 receptor, preventing interaction of HIV and gp120 |
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Nucleoside Reverse Transcriptase Inhibitors
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-Zidovudine, drug against HIV
-inhibits viral reverse transcriptase by phosphorylating themselves intracellularly which competes for synthesis with virus and integrating in viral DNA |
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Non-Nucleoside Reverse Transcriptase inhibitors
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-bind to reverse transcriptase, leading to enzyme denaturation
-can induce cytochrome p450 enzymes, causing a high number of drug-drug interactions -low genetic susceptibility, one mutation in HIV renders drug useless |
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Protease Inhibitors
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-stopping functionalization of virus
-target virus specific protease enzyme, inhibit viral proteases, preventing maturation of virion -Saquinavir or Ritonovir -most effective supressor of viral load -inhibit cytochrome p450 enzymes, causing drug-drug interaction issues and toxicity |
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HAART
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highly activate anti-retroviral therapy
NRTI + NNRTI or PI -combination is more effective |
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Integrase Inhibitors
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Raltegravir
-stops integration of viral DNA into host cell chromosomes -combination therapy for patients with resistant strains -inhibits integrase enzyme |
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Penicillins and Cephalosporins
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-B-lactam antimicrobials
-inhibit transpeptidation reaction during synthesis of peptidoglycan cell wall -bactericidal |
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Administration of Penicillins
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-oral route: rapid elimination, need several doses daily
-parenteral: intramuscular injection |
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Pharmacokinetics of Penicillins
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-penicillins vary in absorption when given orally
-wide theraputic range and nontoxic compared to other antibiotics -widely distributed throughout body -do not enter CSF unless meninges are inflamed |
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Broad-spectrum Penicillins
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-amoxicillin
-more effective against gram-negative bacteria |
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Reversed Spectrum Penicillins
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-greater activity against gram negatives than gram positives
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Adverse Reactions to Penicillin
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hypersensitivity, manifests as:
-skin rashes, fever, anaphylatic shock, serum sickens -gastrointestinal disturbances due to alteration of gut flora -changes in blood clotting |
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Penicillin Resistance
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B-lactamases - can cleave B-lactam ring rendering penicillin inactive. often encoded on plasmids, have developed B-lactamase resistance penicillins
-modification of penicillin-binding proteins (MRSA) |
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Properties of Cephalosporins
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-similar to penicillins in structure and mode of action
-good penetration into CSF -broader specificity against gram-negative bacteria than penicillions. Useful for serious infections such as septicaemia |
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Other B-lactam antimicrobials
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-carbapenems: resistence to B-lactamases and broad spectrum of activity. given by injection
-monobactams: against gram negatives, may not cause hypersensitivity in those allergic to penicillin |
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Sulphonamides
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-earliest succesful antimicrobial agent, now relatively unimportant
-works as a competitive inhibitor of dihydrofolate synthetase, which is involved in bacteria metabolism |
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distribution of elimination of sulphonamides
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-throughout tissues and body fluids, including CSF
-can reach fetal circulation with possible toxicity -metabolized in liver, execreted in kidney -half-life of 10-12 hours |
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Trimepthoprim
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-inhibits dihydrofolate reductase. well absorbed from oral dose. used as single agent for urinary tract and respiratory tract infections.
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Cotrimoxazole
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-used for respiratory and urinary tract infections but trimethoprim alone is now preferred, can be used in combination theory to cut down on resistance
-used for pneumocystis carinii in HIV positive patients |
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Sulfamethoxazole
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-sulfamide used with cotrimoxazale and trimepthoprim
-absorbed and excreted rapidly |
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Tetracyclines
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-bacteriostatic agent
-competes with tRNA for binding to A site of ribosome -wide spectrum of antimicrobial activity, gram positive and gram negative, good against Mycoplasma, Chlamydia -problems with resistence |
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Adverse effects of tetracyclines
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-gastrointenstinal, effect on calicfied tissues, discoloration of teeth, growth effects on bone, hepatotoxicity, photosensitivity
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Erythromycin
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-macrolide antibiotic
-active against gram postive but not gram negative, also good for legionella, mycoplasma and chlamydia -bacteriostatic or bacteriocidal depending on organism -inhibts translation of growing protein chain from A site to P site on ribosome |
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Chloramphenical
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-bacteriostatic
-acts by inhibiting transpeptidation reaction during protein synthesis -broad spectrum of activity -due to toxicity, only for serious infections -resistance bc of chloramphenical actyltransferase |
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Adverse effects of chloramphenical
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-hematological toxicity: low white cell counts due to bone marrow depression, could be fatal
-Grey baby syndrome |
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Aminoglycides
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-mainly active against gram-negative aerobic bacteria, used in treatment of M. tuberculosis
-bactericidal -gives rise to abnormal reading of genetic code during translation ex: gentamycin, streptomycin -highly polar, injection only |
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Adverse effects of aminoglycides
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-ototoxicity: progressive damage to vestibular or cochlear sensory cells
-nephrotoxcity |
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Fluoroquinolones
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-ciprofloxacin
-act by inhibiting bacterial DNA gyrase, preventing negative supercoiling of DNA, which is important in replication -broad spectrum |
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Mycobacterial diseases
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-tuberculosis and leprosy
-present specific problems, slow growth rates, survival within macrophages -increased incidence in AIDS patients |
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Rifampicin
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-reserved for mycobacterial therapy
-binds to RNA polymerase and inhibits transcription -bactericidal -oral dose, induces Cytochrome p450s |
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Isoniazid
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-synthetic agent only active against mycobacteria
-inhibits synthesis of mycolic acid, a cell wall constituent found only in mycobacteria -easily absorbed, widely distributed -metabolized by NAT2 which is absent in 50% of population, leading to peripheral neuritis |
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Treatment of tuberculosis
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-administration of isoniazid, rifampicin and pyrazinamide for 2 months. further 4 months of rifampicin and isoniazid only.
-resistant bacteria may need to include other agents. |
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Selective toxicity
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-use of agents that destroy the parasite but are relatively non-toxic to the host
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Chemotherapy
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-use of synthetic chemicals to destroy infective agents. now broadened to include natural compounds and malignant cells.
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Folate Biosynthesis
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-synthesizes nucleotides, all organisms need this
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Vancomyocin
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-inhibits release of peptidoglycan from lipid carrier, interfering in building of cell wall
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Distributional Selectivity
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-drug that is equally toxic to host and parasite can be useful if the parasite cell is exposed to a higher concentration than the host cell
-achieved by selective accumulation, distribution, administration by parasite |
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Chemotherapy of Fungal infections
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-difficult to treat using selective toxicity bc fungi are eukaryotic
-main targets are cell membrane, cytoskeleton |
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Fungal Infections
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Superficial: candidasis, dermatomycoses
Systemic: systemic candiasis, blastomycosis |
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Routes of administration for antifungal agents
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1. Topical for superficial infections
2. Systemic |
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Azoles
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antifungal agent
-affects membrane lipid synthesis, ergosterol inhibitor -imidazoles, traizoles |
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Polyenes
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antifungal agents that form pores in membrane by binding to sterol and creating ion channel, ergosterol inhibition
-higher affinity for binding to ergosterol in fungi than cholesterol -poorly absorbed, orally for GI infections -Nystatin |
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Mitotic Inhibitors
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antifungal agents that interfere with fungal cytoskeleton. intracellular inhibitor, griseofulvin
-orally in treatments of dermatomycoses |
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Ketoconazole
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-Imidazole antifungal agent
-given orally -causes inhibition of reactions catalyzed by cytochrome p450 in steroid biosynthesis and drug metabolism -hepatotoxicity -safer alternatives, used for severe infections |
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Miconazole
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-Imidazole antifungal agent
=used topically, orally, intravenously -less toxic than ketoconazole, may inhibit drug metabolism |
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Fluconazole
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-antifungal azole,
-orally -achieves high concentrations in CSF, useful in fungal meningitis -non-toxic -like imidazoles does not undergo metabolism and has long half-life |
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Chloroquine
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-antimalarial drug
-accumulates in lysosomes and inhibits digestion of host hemoglobin -oral, few side effects, useful for treatment of clinical attacks and prophylaxis |
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Quinine and mefloquine
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-bind to malarial pigment haemozoin and intercalate into DNA
-useful against erythorcytic, chloroquine-resistance |
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Primaquine
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-antimaralial
-effective for radical cure of exoerythyrocytic forms and gametocytes -metabolized in liver into derivative that are cytotoxic for host and parasites -can cause anemia |
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Proguanil
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-antifolate for prophylaxis for malaria
-Dihydrofolate reductase inhibitor, specific toxicity to plasmodial form, inhibits DNA synthesis |
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Chemotherapy of worm infections
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-interfere with metabolism
-cause paralysis rather than inhibitors of DNA synthesis |
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Mebendazole
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-broad spectrum against a variety of worms
-binds to B-tubulin, preventing polymerization and uptake of glucose by worm -treat roundworm and threadworm infections |
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Praziquantal
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-increased muscular activity in worm followed by contraction and spastic paralysis bc of increased Ca+2 permeability
-against schistosomes and tapeowrms |
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Piperazine
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-oral treatment of roundworm and threadworm
-inhibits neuromuscular transmission of worm -little effects for host |
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Antibody structure
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-basic 4-chain structure, 2 identical heavy chains and 2 identical light chains held together by covalent and non-covalent bonds, and di-sulfide bonds. Each chain has a V and C region. Antigen binding sites consist of heavy and light chain of Variable region. Constant heavy chain interact with effector cells.
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Antibody class
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-class is determined by heavy chain
-each has different function |
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Antibody domains
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-two B-sheets, antiparallel, that lie on top of each stabilized by intra chain disulfide bonds.
-V domain is larger than C, with extra loop. -Domains are paired, folded units with the protein. |
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homology regions
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-analysis of amino acid sequences of H and L chains reveal homology regions, in L chain there are 2 in H chain there are 4.
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immunoglobulin superfamily
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-immunoglobulin-like domains present in this whole range of toher proteins.
-includes TCR, MHC class I and II, various other molecules |
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Fab region
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The fragment antigen-binding (Fab fragment) is a region on an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain
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Fc region
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The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system.
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Hypervariable regions
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-3 hot spots of variability
-hypervariable regions form antigen binding site, 3 from light chain and 3 from heavy chain - |
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Antigen recognition
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-epitopes recognized by antibodies can be sequential or conformational (discontinuous)
-antigens can be various macromolecules (proteins, polysaccharides) |
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T-cell receptor structure
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-heterodimer of a and B chain, each having a V and C region
-Ig like domains -V domains interact with antigen, a peptide bound to MHC molecule -each chain contributes 3 CDRs(hypervariable regions) |
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MHC
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-two types, MHC class I and II
-present peptides from different sources, many genetic variants -role in transplant rejection |
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MHC Class I
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-three different types, different alpha chains which are coded by three different genes: HLA-A, HLA-B and HLA-C.
-heterodimer: a chain, B2 microglobulin a1 and a2 domains form peptide binding site, only alpha chains are polymorphic. -peptides are bound to MHC by ends, have to fit in, 8-9 peptides |
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MHC Class II
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-three types: HLA-DP, -DQ and -DR
-heterodimer, a and B chains are similar size and both transmembrane. Both chains are polymorphic and encoded by MHC genetic region. top proteins form peptide binding site, bottom proteins Ig-like. -has space for peptide to hang out of, ends of peptide are not bound |
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Multiple genes encode a single polypeptide chain
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-V and C regions of antibody and TCR polypeptide chains are encoded by separate gene segments that rearrange during lymphocyte differentiation
-H chain and TCRB: V region encoded by three gene segments: VDJ -L chain and TCRa: V region encoded by two gene segments: V and J |
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Heiarchy of rearrangements
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-first H chain genes (D-J then V-D)
-then light chain genes (V-J). |
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Recombination Signal Sequences
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-DNA rearrangement is guided by special sequences flanking the V,D and J regions.
-Involves a complex of enzymes = V(D) J recombinase |
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Rag1 and Rag2
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-required for rearrangement of immunoglobulin genes
-RAG1 and RAG2 genes encode lymphoid specific components of the recombinase -mutations in RAG result in immunodeficiency |
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Allelic exclusion
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-in a single B cell only one allele of H chain expressed, similarly for L chain
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Rag1 and Rag2
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-required for rearrangement of immunoglobulin genes
-RAG1 and RAG2 genes encode lymphoid specific components of the recombinase -mutations in RAG result in immunodeficiency |
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Light chain isotype exclusion
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-a single B cell expresses either K or lambda, never both
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Allelic exclusion
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-in a single B cell only one allele of H chain expressed, similarly for L chain
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Mechanisms for generation of Antibody diversity
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1) multiple germline genes: multiple VH, VΚ and Vλ, multiple D and J
2) combinatorial diversity: due to D segments, H chains potentially more diverse than L chains 3) Junctional diversity: imprecise joining, N regions 4) Combinations of heavy and light chains 5) Somatic hypermutation |
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Light chain isotype exclusion
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-a single B cell expresses either K or lambda, never both
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N regions
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mechanism for generation of antibody diversity, N regions are random addition of nucleotides at junctions of VD and DJ by terminal transferase
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Mechanisms for generation of Antibody diversity
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1) multiple germline genes: multiple VH, VΚ and Vλ, multiple D and J
2) combinatorial diversity: due to D segments, H chains potentially more diverse than L chains 3) Junctional diversity: imprecise joining, N regions 4) Combinations of heavy and light chains 5) Somatic hypermutation |
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N regions
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mechanism for generation of antibody diversity, N regions are random addition of nucleotides at junctions of VD and DJ by terminal transferase
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Somatic hypermutation
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-mutation frequency in antibody VH genes is much higher than normal spontaneous mutation rate
-occurs in germinal centers after activation of B cells by antigen -involves AID enzyme |
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AID enzyme
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-involved in somatic hypermutation to generate antibody diversity, AID acts on DNA to deaminate cytosine to uracil. Uracil is recognized by error-prone DNA repair pathways leading to muations
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Membrane vs. secreted antibody
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-secreted form of antibody has an alternative hydrophillic C-terminus but same specificity as membrane Ig
-membrane and secreted forms produced by alternative RNA processing |
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T cell receptor genes
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-TCR polypeptides encoded by rearranging genes, variable regions encoded by V,D & J segments
-gene segments rearrange during T cell development in the thymus -mechanism similar to Ig gene rearrangement: similar recombination signal sequences and enzymes involves |
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Generation of diversity of TCR
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similar mechanisms to Ig
-multiple VD and J gene segments, combinatorial diversity between V,D and J, junctional diversity -NO somatic hypermuation |
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MHC genes
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-don't rearrange, located within MHC (HLA in humans)
-co-dominantly expressed -class I on all nucleated cells, Class II on particular cell types such as B-cell, macrophages, dendritic cells -up regulated by interferon |
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Co-dominant expression of MHC
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-three class I loci (HLA-A, HLA-B, HLA-C). If heterozygous at each, can express six different class I molecules.
-similarly for class II (HLA-DP, HLA-DQ and HLA-DR) |
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MHC polymorphism
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-extends the range of peptides that can be presented to T cells
-is responsible for graft rejection -genetic influence on some diseases such as autoimmune diseases |
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Exogenous vs. Endogenous antigens
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-endogenous antigens (proteins made in the cytoplasm) are presented by class I molecules
-exogenous antigens are presented by class II -in both cases protein must be processed to peptides before binding MHC |
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Presentation by MHC class I
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1) Antigen synthesized in cytoplasm
2) protein cleaved to peptides by proteasome 3) Peptides transported to endoplasmic reticulum by TAP transporter 4) Peptides bind to MHC class I molecules 5) MHC peptide complex transported to cell surface |
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TAP Transporter
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-involved with presentation of peptides by MHC class I
-transports peptides to endoplasmic reticulum where they can bind to MHC -component of peptide loading complex |
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Presentation by MHC class II
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1) Antigen endocytosed into intracellular vesicles
2) Protein cleaved to peptides by acid proteases 3) Vesicles fuse with vesicles containing class II MHC 4) peptides bind class II MHC 5) MHC-peptide complex transported to cell surface |
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HLA-DM
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-binds to the MHC class II molecule, releasing CLIP of proteins and other other peptides to bind. chaperone protein that binds to MHC II molecule and invariant chain.
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calnexin
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-chaperone protein involved in assembly of MHCI in ER
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Expression of MHC
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-all nucleated cells have MHC class I molecules, so any body cell infected by virus can be killed by cytotoxic T cells
-only a limited number of cells express class II: these include the professional antigen presenting cells which activate helper T cells (macrophage,s, dendritic cells, B cells) |
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General Path of B cell development
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-develop from haematopietic stem cells in bone marrow
-continous process, many produced per day -involves rearrangment and expression of Ig genes and other markers -removal of self-reactive cells |
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B-cell expresses either kappa or lambda
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light chain genes, one or the toher
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Bone marrow stromal cell
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-non-lymphoid cells
-essential for B-cell development, cell-cell contact via adhesion molecules and synthesis of growth factors |
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TdT
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-terminal transferase
-this is the enzyme that will add nucleotides in random manner that is important in generating junctional diversity |
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General Path of B cell development
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-develop from haematopietic stem cells in bone marrow
-continous process, many produced per day -involves rearrangment and expression of Ig genes and other markers -removal of self-reactive cells |
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VpreB
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-surrogate light chain components
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B-cell expresses either kappa or lambda
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light chain genes, one or the toher
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Bone marrow stromal cell
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-non-lymphoid cells
-essential for B-cell development, cell-cell contact via adhesion molecules and synthesis of growth factors |
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TdT
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-terminal transferase
-this is the enzyme that will add nucleotides in random manner that is important in generating junctional diversity |
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VpreB
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-surrogate light chain components
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Btk
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-B cell tyrosine kinase
-important in development, without presence B-cell development is blocked -immunodeficiency disorder in boys, x-linked, boys can't make B-cells |
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Tolerance in immature B cells
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Immature B-cells that
-bind multivalent self-antigen undergo either clonal deletion or receptor editing -bind soluble self-antigen -> cell becomes anergic |
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T cell development
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-same as B cell except
-undergo development in thymus -alternative lineages (CD4 or CD8) -must be able to interact with self MHC -> positive selection |
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Thymus
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-bilobed organ in chest
-contains lymphoid cells, epithelial cells, macrophages and dendritic cells |
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T cell maturation in thymus
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-prothymocytes enter cortex via blood vessels
-rearrange TCR genes: first for beta chain, then cells proliferate and rearrange genes for alpha chain of TCR -express TCR together with CD3, also express CD4 and CD8 |
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CD3
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Expression of TCR requires CD3, role in singal transduction
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γδ TCR
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-similar structure to aB receptor
-expressed on separate T cell population, 1-5% in circulation, majority in epithelial tissues -recognize different antigen from conventional aV T cells -lineage commitment to aB or yδ depends upon which genes are first to rearrange successfully |
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Positive selection
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-positive selection of T cells which recognize self MHC
-occurs when double positive (CD4+CD8+) T cells recognize MHC on cortical epithelial cells -rearrangment gives random TCR repertoire -most fail, cell with non-binding TCR die -positively selected cells move to medulla |
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Negative selection
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-negative selection of cells which recognize self MHC on dendritic cells/macrophages with high affinity
-present variety of self peptides with MHC class I and II -TCR binding to MHC/peptide causes cell death by apoptosis |
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Mature Phenotype of T cells
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Double positive CD4+CD8+ cells acquire mature phenotype
-if recognize peptide +class I: lose CD4 -if recognize peptide + class II: lose CD8 |
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Avidity hypothesis
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-T-cells positively and negatively select for self MHC+peptide
-Why aren't all T cells that were positively selected eliminated during negative selection? -all T cells recognizing self MHC are positively selected -those with highest affinity TCR are then negatively selected, resulting in a population of T cells with low affinity for self peptide + self MHC but high affinity for foreign peptide +self MHC |
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T-cell immunity
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-Virgin T cells recirculate via secondary lymphoid tissue
-contact with specific antigen and APC triggers clonal proliferation and differentiation -Effector T cells: Cytotoxic (CD8) kill infected cells and Helper cells (CD4) secrete cytokines |
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Lymphoid tissues
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-T cell must bind antigen on antigen presenting cell (APC)
-Occurs in secondary lymphoid tissues, lymph nodes, spleen -effectors then migrate to site of infection |
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CAMs
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Cell adhesion molecules
-present on T cell, binds ligands on other cells -different sets mediate different interactions: -naive T cell with high endothelial venules -T cell with antigen presenting cells -effector T cell and target cell |
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Co-stimulation in T-cells
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-signal from TCR containing MHC/peptide (signal 1): involves CD3 and zeta
-second, co-stimulatory, signal required for activation -APC express co-stimulator molecules -B7 on APC delivers co-stimulation signal to CD28 on naive T cells, resulting in CD28 cross-linking and inducing expression od CTLA-4. |
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CTLA
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-CTLA-4 binds B7 more avidly than CD28 and delivers inhibitory signals to activated T cells
-CTLA4 mutations associated with several autoimmune diseases -limits proliferation of T cells |
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B7.1 and B7.2
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-APC molecules that provide costimulatory signals for T-cells necessary for activation
-expression of co-stimulator molecules vary: constitutive on mature dendritic cells, inducible on macrophages, B cells -costimulatory signal must come from same cell that presents MHC/peptide |
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Activation of APC
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-danger signal needed to ensure response only during ingetions
-signal activates APC, causing upregulation of MHC and co-stimulator molecules |
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Peripheral tolerance
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-in the absence of infection no co-stimulator molecules are expressed, no second signal, so T cells are inactivated
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APCS deliver three kinds of signals to naive T cells
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CD4+MHC classII -> activation
B7+CD28 -> Survival cytokines IL-6, IL-12, TGF-B -> differentiation |
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Professional APCs
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Dendritic cells
can also be Macrophages and B cells |
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Dendritic cell as APC
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-principle antigen presenting cells that initiate T cell responses
-induced to mature and migrate to lymph node after antigen contact -located throughout body |
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Macrophages as APC
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-mainly function as scavengers of pathogens but can also present antigen
- MHC class II and B7 can be produced only when induced by danger signals like LPS -located in lymphoid, connective tissues and body cavities |
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B-cell as APC
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-act as a specific way, endocytosis of antigens attached to surface immunoglobulin receptors
-co-stimulator induced by danger signals like bacterial lipopolysaccharide -located in lymphoid tissues and blood |
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Interleukin-2 (IL-2)
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T-cell growth factor
-secreted by activated T cells, which have high affinity IL-2 receptors -IL-2 binding to IL-2R induces T-cell proliferation -target of immunosuppressive drugs, knock out IL-2 knock out T-cell response |
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Properties of Effector T-cells
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-display effector function when TCR is engaged, no longer require co-stimulation
-change expression of adhesion molecules, no longer enter lymph nodes, enter tissues via activated endothelia at sites of infection and inflammation |
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B-cell activation
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-virgin B cells express IgM
-encounter antigen in secondary lymphoid tissue -signal 1: crosslinking of sIg -signal 2: if TD, T-cells If TI, antigen or extensive crosslinking of sIg |
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TI-1 antigens
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-bind to receptors on B cells (signal 2), causing proliferation and antibody secretion
at high concentrations can act as polyclonal activators for B cells |
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TI-2 antigens
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-repeated epitodes, often polysaccharides, important for some bacterial infections
-extensive cross-linking of sIg important in signalling -additonional signals may come from dendritic cells in the form of BAFF (B-cell activating factor) -response develops after age 5 (need conjugate vaccines) |
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TD antigens
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-prtoeins
-T cell activated by MHC/peptide on APC -B bell sIg binds antigen -> signal 1 then processes and presents antigen to CD4 T-cells -> signal 2 |
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CD40
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CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.
-CD40 signal also induces AID, required for class switching and somatic hypermutation |
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B-cell acts as APC for TD antigens
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-epitopes recognized by antibody and T cell can be different parts of molecule, different molecules of complex (viral proteins)
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Conjugate vaccines
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-allow T-cell help for polysaccharide based antigens by conjugated to a protein
-allows young children to be immunized |
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Interactions between B and T cells
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-initially occurs in T cell areas
-Activated T helper cell expresses CD40L, secretes cytokines -signals through CD40 and cytokine receptors drive B cell proliferation -CD40 signal also induces AID, required for class switching and somatic hypermutation |
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Fc Receptor (FcR)
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Their activity stimulates phagocytic or cytotoxic cells to destroy microbes,
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Germinal center cells
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- Maturing B cells that either differentiate to plasma cells, form long-lived memory cells, or die within lymphoid tissue
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FDC
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follicular dendritic cells
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Affinity maturation
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affinity maturation is the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response can elicit antibodies with several logfold greater affinity than in a primary response.
-die by apoptosis unless sIg binds antigen on FDC or receive CD40 signal from Th cell. centrocytes compete for FDC antigen, higher affinities selected. |
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Hyper IgM syndrome
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-abundance of IgM, but cannot class switch so only one kind of antibody. caused by CD40L deficiency and AID deficiency.
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Control of isotype switching
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-different antigens induce different isotypes:
polysaccharides: IgM, IgG2 proteins: IgG1, IgG3, IgG4 -antigens at mucosal surface induce IgA -cytokines important: IL4 induces IgE |
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Lymphocytes become tolerant bc
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1) they encounter antigen in central lymphoid organs when they are immature (central tolerance)
2) they encounter antigen in the peripheral tissues in the absence of other signals (peripheral tolerance) |
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AIRE
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-autoimmune regulator protein
-allows expression of tissue-specific antigens in thymus. important for tolerance induction. deficiency causes an autoimmune symdrome |
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Receptor editing
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-immature B cells that bind self antigen may undergo further light chain rearrangments as there is a possibility of expressing a receptor that is not self-reactive
-similarly, T cells can undergo receptor editing |
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Tolerance through clonal anergy
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-lymphocytes that recognize self antigens are rendered unresponisve ie anergic
-T cells: when Ag receptors cross link in absence of second signal/costimulator -B cells: when receptors encounter Ag that is not multivalent |
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Peripheral tolerance of T cells
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-infections produce co-stimulator molecuels ensuring T cells are active only in infections. without signal T cell becomes anergic.
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Priveleged Sites
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difficult to induce an immune response, antigens are sequestered from immune system and suppressive cytokines are prevalent
-eye, testis, CNS |
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Regulatory T cells
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subset that suppress immune responses. important in tolerance and supressing autoimmune responses. Arise in thymus from T cells with high affinity receptors for self antigen.
-deficiency of Treg cells causes autoimmune syndrome IPEX, which is chronic and not curable |
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Qualitative regulation of responses
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-T cells play a major role in determining what type of immune response is made
-Th1-> activation of macrophages, NK cells, cytotoxic T cells -Th2-> antibody responses, especially IgE, IgA. |
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gamma-interferon
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cytokine TH1 uses to activate macrophages
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Activated macrophage
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-increases microbial activity -> increased fusion of phagosomes with lysosomes and increased synthesis of oxygen radicals, NO, proteases
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IL-12 and gamma interferon
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-key role in indiction of Th1 responses, determination of type, for intracellular infections
-makes CD4 T cells differentiate into Th1 |
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IL-4
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induction of Th2 responses, antibody production
makes CD4 T cells differentiate into Th2 cells |
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Th17
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-secrete IL-17
-recently identified subset of CD4 T cells -function to recruit neutrophils early in infection -implicated in autoimmune disease |
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Treg: Mode of Action
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-may involve cytokines TGF-B and IL-10, may require cell to cell contact
-can act on other T cells or on APCs to downregulate function |
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Clinical significance of Treg
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-autoimmune disease, allergy, allograft rejection, tumour immunity, infection
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IL-10
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It down-regulates the expression of Th1 cytokines, MHC class II antigens, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production.
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TGF-B
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Transforming growth factor beta (TGF-β) is a protein that controls proliferation, cellular differentiation, and other functions in most cells
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