Immunology Flashcards
Two types of immune responses
Innate
- components already at location of infection, and respond immediately with a generalised response.
Adaptive/specific
- T and B cells located away from the infection.
- When respond they do so in a specialised way to specifically target the pathogen
- takes longer
Complement system works alongside these two responses.
Initial immune response
- Macrophages recognise pathogen and activate the immune system.
- Dendritic cells pick up antigens from pathogen and travel through the blood and lymphatic system to locate the specific T and B cells and activate them.
- Invading pathogen activates the complement system through the lectin and alternative pathways.
Innate immune system - macrophage actions
- Macrophages recognise pathogens through pathogen associated molecular patterns (PAMPs) on their surface. Through phagocytosis they recognise and detroy pathogens.
- If the pathogen assault is too great for this to work alone, macrophages release cytokines (signalling proteins - which triggers a localised inflammatory immune response).
Innate immune system - cytokines
signalling proteins - which triggers a localised inflammatory immune response.
Cytokines recruit and activate more cells of the innate immune system - macrophages, monocytes (precursors to macrophages) and neutrophils (another phagocyte).
The inflammatory process driven by cytokines causes vasodilation, increased vascular permeability, mast cell degradation, clotting system activation and kinin system activation. Cytokines release interleukins as part of this inflammatory response.
This process of localised inflammation is called the acute phase reaction.
This leads to systemic inflammation.
Acute phase response
Process of localised inflammation from cytokine activation and interleukin production causing a systemic inflammatory response.
IL-1 release - acts on brain to cause fever, decreased appetite and lethargy
IL-6 release - acts on liver to release acute phase proteins (opsonins - eg CRP)
IL-8 release - recruits and activates neutrophils
IL-2 and IL-12 - activate natural killer cells.
TNF-alpha does all the above by itself.
Complement system
Complement proteins C1-C9
Proteins activate each other in the complement cascade.
These work by activating opsonins, causing inflammation and destroying pathogens.
The complement system is activated either directly by the pathogens (lectin and alternative pathways activate) or through antibody-antigen complexes (classical pathway).
Adaptive/specific immune system.
B and T cells are lymphocytes which make up the adaptive immune system.
Found in the lymphatic system, sequestered in lymph nodes waiting for invading pathogens.
Dendritic cells travel from the site of the pathogens infection carrying antigens and display them on their cell surface on HLA class II molecules. This is then presented to the T and B cells until the correct ones are found and activated.
T cells
Every pathogen has antigens unique to them they express on their surface.
Each T cell has T cell receptor on it’s surface specific to a single antigen.
CD4 T cells are activated by the dendritic cells presenting the correct antigen on the HLA class II molecules.
CD4 T cells then proliferative and become T helper cells. These present the antigen on their HLA class 1 molecule which is recognised by CD8 T cells.
The T helper cells also release cytokines which cause the CD8 cells to proliferative and turn into cytotoxic T cells.
Cytotoxic T cells kills cells that have been infection by pathogens (i.e. virally infected cells).
The T helper cells also travel to the the site of the infection and release cytokines to stimulate the innate immune system further.
B cells
Every pathogen has antigens unique to them they express on their surface.
Each B cells has antibodies on it’s surface specific to a single antigen.
T helper cells release cytokines that activate B cells and turn them into plasma cells - these make antibodies and Memory B cells which form the immune memory for future infections.
Antibodies
Produced by plasma cells (differentiated B cells) - part of adaptive immune system.
Y shaped protein- variable region which matches different antigens, other end is fixed in shape and can be recognised by various cells in the immune system.
1. Attach to enemy toxins (antigens) and neutralise their effect
2. Attach to the antigen receptors on pathogens and prevent them from carrying out their function (can prevent the viral invasion)
3. Attach themselves to pathogens and cause aggultination which slows their spread down
4. Can act as opsonins to the pathogen and help the macrophages and neutrophils to recognise and phagocytose them.
What are natural killer cells, including different subsets which are relevant to reproductive medicine. What is their normal function.
Lymphoid progenitor cell.
Part of the innate immune system.
Have uterine and peripheral subsets.
Uterine - CD56birght, CD16-ve, high KIR, low cytotoxicity,
Peripheral - CD56dim, CD16+ve, low KIR, high cytotoxicity,
Peripheral NK involved in cell death - namely viruses and cancer cells. Don’t require APC priming or MHC presentation. Release perforin and granzymes, secrete cytokines.
uNK - involved in implantation, vascular remodelling and trophoblastic invasion
How are NK cells tested and reported
pNK - blood test - flow cytometry
uNK - endometrial biopsy - immunofluorence, or flow cytometry.
- varies widely during menstrual cycle, usually taken in the luteal phase, can be reported as number or percentage of circulating lymphocytes or total stromal endometrial cells.
Theories behind NK cells and infertility
- increased uNK levels may cause increased production of angiogenic factors leading to increased peri-implantation blood flow and excessive oxidative stress to trophoblast cells.
- Other evidence suggests that uNK have a predisposition to secrete pro-inflammatory cytokines akin to Th1-type cytokines while dampening anti-inflammatory Th2-type cytokines that are necessary to maintain healthy pregnancy.
- Different combinations of parental HLA-C and maternal KIR allotypes on livebirth outcome in women undergoing ART has highlighted that inadequate, rather than excessive, activation of uNK may be the cause of RPL and RIF.
uNK very important in spiral artery remodelling alongside macrophages
uNK KIR and HLA
KIR (Killer-cell immunoglobulin like receptors) are receptors found on NK cells.
HLA-C is the only MHC1 complex presented on extra-villous trophoblast.
It has been postulated that an adequate interaction between maternal KIRs and their ligands, the HLA class I molecules, expressed by the extravillous trophoblast cells is crucial for sustained implantation.
By binding to HLA-C KIRs either promote or inhibit NK cell activity.
An increased risk of RIF is observed in women carrying the HLA-C2 allotype and the HLA-G allele with a 14 bp insertion.
Possible immune therapies listed in ESHRE RPL guideline and recommendation
Lymphocyte immunisation therapy - should not be used as it has no significant effect and there may be serious adverse effects (++– strong).
Intravenous immunoglobulin (IVIG) - repeated and high dose IVIG very early in pregnancy may improve LBR in women with 4 or more unexplained RPL (++– conditional)
Prednisolone - not recommended as a treatment (++–strong)
Anticoagulants - heparin and LDA are not recommended, they don’t improve LBR. (+++- strong)
Intralipid therapy - Insufficient evidence to recommend intralipid therapy for improving LBR (+— strong).
G-CSF - No evidence to recommend G-CSF (+++- strong)
