Immunology 1 Flashcards
(46 cards)
Primary lymphoid organs
· Where lymphocytes (B, T and NK cells) are produced
· E.g. à thymus, bone marrow, foetal liver
· B cells produced in bone marrow – bone marrow is primary site of haematopoiesis
· Immature T cells formed in bone marrow and migrate to thymus to mature
Primary lymphoid organ - T Cell Selection in Thymus
o Stepwise differentiation
o Positive selection à can the TCR signal?
o Negative selection à does cell react against our own body? – important as this protects against autoimmune disease
o Final selection and exit
· Thymic involution è thymus shrinks/atrophies as we age, functional tissue gets replaced w/fat
o total thymic output of new T cells decreases BUT no. T cells in repertoire stays the same
Secondary lymphoid organs - Spleen
o Filter antigens that are found in the blood
o White pulp = lymphoid tissue
o Distinct T and B cell zones
o Afferent and efferent lymphatic vessels
o Arterial and venous connections
Secondary lymphoid organs - Lymph nodes
o Act as filters and slow down flow of lymph
o Contain lymphocytes which can trap + phagocytose any foreign antigen
o Lymph enters via afferent lymphatic vessels and leaves via efferent
o B and T cells enter and leave via systemic circulation
o Diff. regions for B and T cells
o Medullary sinus à macrophages, direct to T cell or B cell area depending on response needed
Secondary lymphoid organs - Mucosa associated lymphoid tissue (MALT)
o Defends epithelium
o Specialised tissues called Peyer’s patches in gut (large collection of lymphocytes – mainly B cells)
o Cutaneous immune system e.g. Langerhans cells (type of DC)
Secondary Lymphoid organs
· Where lymphocytes can interact with antigens and other lymphocytes
· E.g. à spleen, lymph nodes, appendix, mucosal associated lymphoid tissue – all interconnected via lymphatic system and blood
· Bring cells in close proximity to antigen
Dendritic cells
· Dendritic cells present antigens
· Migrate to lymph nodes via afferent lymph vessels
· Present antigens to T cells
· T cells enter lymph nodes through high endothelial venules and move around within T cell area à transiently interact w/large no. of dendritic cells à leave node via efferent lymphatic vessels
Characteristics :
APC
Bridge between innate and adaptive immune systems
Effective against : For activation of adaptive immunity
Activating factors : Phagocytosis
Recogition of PAMPs
Effector mechanism : Costimulatory molecules
Upregulate MHC
Cytokine secretion
Migrate to lymph node for T cell maturation/ B cell
Lymphotcytes
Summarise how T-lymphocytes and B-lymphocytes recognise antigen and are subsequently activated.
· Repertoire à range of genetically distinct BCRs or TCRs
· Antigen à molecules that induce an adaptive immune response, mostly protein, large signalling molecules normally not found in the body which act as ‘red flags’ activating the immune system
· Epitope à small areas of molecular structures of foreign antigen
B Lymphocytes
· Humoral immunity
· B cell receptor: membrane bound antibodies (membrane bound antibody will be the same as that produced by activated plasma cell)
· Activated to become plasma cells which produce antibodies à neutralisation, opsonization, agglutination
o NEUTRALISATION è antibody prevents bacterial adherence
o OPSONIZATION è antibody promotes phagocytosis
o COMPLEMENT ACTIVATION è antibody activates complement, which enhances opsonization and lyses some bacteria
Antibodies
o 4 protein chains à 2 heavy + 2 light
o Made of Fab and Fc regions
o Linked by intermolecular disulphide bonds
o Each heavy chain has variable and constant region
§ CONSTANT REGION – identical in all antibodies of same isotype/class, but differs in antibodies of diff. isotypes
§ VARIABLE REGION – differs depending on B cell that produce it, but is same for all antibodies produced by single B cell or B cell clone
o 5 types à IgG (most common), IgA (dimer), IgM (pentamer), IgE, IgD
§ Antibody isotypes/classes differ in biological properties, functional locations and ability to deal w/different antigens
o First BCR is an IgM
IgG
· Most prevalent antibody molecule in serum
· Survives intact om serum for longest time
· Able to cross placenta to allow maternal protection of newborn
· Important in cell-mediated cytotoxicity, fighting viruses and toxins
IgA
· Main Ig in secretions (saliva, breast milk, tears) and mucosal epithelia (respiratory, genital and intestinal tracts)
· Dimeric in secretions – consists of 2x IgA molecules, J chain and molecule of secretory component which protects molecule from proteolytic attack + facilitates its transfer across epithelial cells into secretions
IgM
· Predominant antibody in early immune response
· Pentameric structure – 5 Ig units held together by J chain and disulphide bonds
· 10 potential antigen binding sites so very efficient at agglutination of bacteria and activation of complement pathway
IgE
· Involved in protection against parasitic infections
· Binding of antigen to IgE coupled w/an Fc receptor on mast cells and basophils è triggers an allergic reaction by activation of mast cells and release of mediators like histamine
IgD
· Mainly found on surface of B cells as receptor molecules (BCR)
· Involved in B cell activation
Antibodies variations
Diff B cells produce antibodies w/ diff. antigen-binding regions – diversity achieved by immunoglobulin gene rearrangement
· Somatic recombination à process of gene segment rearrangement that occurs to create a repertoire of antigen receptors
o As B cell develops, unused genes in each array are cut out so that only one gene of each multigene family/region gets passed down
· VDJ and VJ recombinases are responsible for looping and cleavage of immunoglobulin genes – also randomly add or remove nucleotides to create a viable joint between both DNA fragments
o Heavy chain undergoes VDJ rearrangement first
o Then light chain undergoes VJ rearrangement
· VDJ recombinase cuts extra genes we don’t want, splices together 2 wanted genes (variable + joining genes variety creates diversity)
· SCID (severe combined immunodeficiency) – due to mutations in genes coding for V(D)J recombinase - characterised by variation of VDJ enzymes
· Diversity generated by:
o 1. Germline diversity
o 2. Combinational diversity
o 3. Junctional diversity
o 4. Heavy + light chain diversity
o 5. Somatic hypermutation – antigen induces point mutations in variable regions
· Negatively select self-reactive B cells
· B receptor is a membrane bound antibody paired w/accessory immunoglobulin heterodimer to enhance signal transduction
Activation of B cells
o B cell activated by antigen binding to IgM BCR
o Short-lived plasma cell produced to trigger apoptosis OR germinal centre formed à long-lived plasma cell, memory B cell (using affinity selection or class-switching)
o Germinal centre
§ Specialised structure within which B cells undergo rounds of proliferation accompanied by affinity maturation
§ Iterative process of
o T cell independent activation
§ Polysaccharides on surface of bacteria + binding to antigen itself
§ Don’t need T cells
§ Only IgM
§ No memory
§ Repeating carbohydrate subunits on bacteria (bacterial polysaccharides, cell wall components) engage multiple BCRs overcoming the need for a second signal
§ No affinity maturation nor class switching (only low affinity IgMs)
o T cell dependent activation
§ T cell has recognised antigen and binds to B cell
§ Initiates greater immune response
§ All Ig classes
§ Has memory
§ Antigen engulfed and processed by B cell and by dendritic cell which express on their surface à recognised by T helper cells à cytokine release à B cell activation (rapid division and differentiation into plasma or memory cells) + class switching
T Lymphocytes - T helper cells (CD4)
release cytokines to induce a response from other immune cells
o Main ones include Th1, Th2, Treg, Th17, Tfh
o Th1 à pro-inflammatory, boost cellular immune response è IFN gamma, TNF, IL-12
o Th2 à pro-allergic, boost multicellular response è IL-4, IL-5, IL-13
o Tfh à pro-antibody è IL-21
o Th17 à pro-inflammatory, control bacterial and fungal infection è IL-17, IL-23, IL-6
o Treg (Th0) à anti-inflammatory, limits immune response è IL-10, TGF beta
T lymphocytes - cytotoxic T cell (CD8)
kill infected cells or tumour cells by inducing apoptosis (3 major mechanisms to kill infected or malignant cells)
o 1. Secrete IFN gamma and TNF
§ Have anti-tumour and anti-viral microbial effects
o 2. Production and release of cytotoxic granules
§ Cytotoxic granules (also found in NK cells) contain 2 families of proteins à perforin and granzymes
§ Perforin à forms pore in membrane of target cell, similar to MAC of complement
§ Pore allows granzymes also contained in granules to enter infected or malignant cell
§ Granzymes à serine proteases which cleave proteins inside cells, shutting down production of viral proteins + ultimately resulting in apoptosis of target cell
§ 1. Granule exocytosis
§ 2. Perforin injected on target cell surface
§ 3. Pore opened
§ 4. Granzymes into cell activating caspase enzyme à apoptosis
o 3. FAS – FAS Ligand interactions
§ Activated CD8+ T cells express Fas ligand which binds to Fas receptor on surface of target cell
§ Binding causes Fas molecules on surface of target cells to form a trimer which pulls together signalling molecules
§ Signalling molecules result in activation
§ Because CD8+ T cells can express both molecules, Fas/FasL interactions are a mechanism by which CD8+ T cells can kill each other à used to eliminate immune effector cells during contraction phase at end of immune response
Major Histocompatibility Complex (MHC) and T cell receptors (TCR)
· MHC haplotype à combination of MHC alleles found together on a single chromosome
· TCR like Fab (variable) part of antibody à beta homologous to heavy chain, alpha to light etc.
o All TCRs associated w/CD3 complex – important in signal transduction
o Recognise antigens which have been taken in, processed and presented on surface of APCs (B cells, dendritic cells, macrophages)
o Antigen presented on MHC
o TCRs also have co-receptors e.g. CD4, CD8 which stabilise MHC-TCR binding
· MHC is polygenic and polymorphic
o Several class I and class II loci
o Diff. genes for one thing à diff. genes combine to form diff. classes
o MHC is highly polymorphic à lots of alleles – ensures wide variety of MHC to recognise diff. pathogens
o Ensures wide variety of MHC to recognise diff. pathogens
CD4 works with MHC II
o 2 transmembrane proteins
o Present in professional APCs only
o Accommodates longer polypeptides
o Presents extracellular antigens
§ 1. Extracellular antigen phagocytosed into an endosome
§ 2. Endosome fuses w/lysosome and antigen is digested
§ 3. In meantime MHC II synthesised in ER, invariant chain blocks peptide binding groove
§ 4. Vesicle containing MHC II buds from ER and fuses with lysosome
§ 5. IC degraded allowing MHC II-antigen complex to form
§ 6. Complex transported to and expressed on cell surface
CD8 works with MHC I
o Present in all nucleated cells
o 1 transmembrane component
o Accommodates shorter polypeptides
o Presents intracellular antigens
§ 1. Proteins from intracellular pathogen digested by a proteasome
§ 2. Antigen peptides are transported via TAP (transporter associated w/antigen presentation) into ER
§ 3. In the meantime, MHC class I synthesised in ER
§ 4. Within the ER, MHC I – antigen complex forms
§ 5. Complex transported to and expressed on cell surface
Bacteria
· Prokaryotes
· No internal membranes
· Haploid à single copy of chromosomes in cytoplasm
· Different organelles e.g. 70s ribosome
· Poorly defined cytoskeleton
· Cell wall contains peptidoglycan à can have diff. shapes e.g. coccus, rod etc.
· Divide by binary fission
· Can use flagellum to move
· Examples:
o Shigella – faecal-oral transmission
o Neisseria meningitidis – rapid progression, septic shock, severe inflammatory response
o Clostridium difficile + MRSA – hospital acquired
o TB
o Leprosy – transmitted by nasal discharge
o E. Coli
· NEISSERIA MENINGITIDIS:
o Gram -ve diplococci
o Nose and throat commensal
o Causes meningitis
o Symptoms à headaches, photophobia, sepsis, 10% fatality, can infect immunosuppressed
· MYCOBACTERIUM TB:
o Intra-cellular rod
o Causes TB
o Respiratory disease but can be systemic
o Abscesses
o Very hard to treat, can be lifelong
Viruses
· Obligate parasites
· Contain RNA or DNA (single or double stranded)
· Use host cell machinery to replicate à ribosomes etc.
· Divide by budding out of host cell or cytolysis
· Transmission à blood (HIV, hepatitis), airborne (influenza), vectors, faecal-oral
· Examples:
o HIV
o Smallpox
o Polio
o HPV
· HIV
o ssRNA virus
o reverse transcriptase (turns RNA into DNA to insert into host genomes)
o infects T cells
o leads to AIDs
o very low CD4 T cell count à increased risk of infection
