Barrier Immunity Flashcards
what do barrier organs protect?
the internal surfaces
what are the immune systems associated with mucosal tissues (MALT)?
- gut = GALT
- respiratory tract (includes the nasal and bronchial tract)
what are the physical mechanisms of mucosal protection?
- one or more layers of epithelial cells
- mucus layer
- pH and osmotic control
- cilia
- antimicrobial peptides
- sensor cells/ tuft cells
what are the two main goals of GALT?
to clear pathogens and maintain homeostasis
what is GALT tolerance promoted by?
oral tolerance and bystander suppression
organs that have GALT:
tonsils
adenoids
peyer’s patches
esophagus
appendix
what else does the epithelial layer do, than just provide a physical barrier?
sends signals to the underlying immune system, alarmins
what are the two types of signals that trigger the immune system?
- PAMPS (pathogen associated molecular patterns)
- DAMPS (damage-associated molecular patterns)
what are some examples of DAMPS?
alarmins, pH, salt, CO2, etc
what pathogens are responsible for type 1 immunity?
- viruses
- bacteria
- fungi
- protozoa
what pathogens are responsible for type 2 immunity?
- helminth
- allergens
- venoms
what molecules do the microbiota produce that are recognized by the immune system?
- short chain fatty acids
- vitamins
- histamine
- glycoproteins
- microbial peptides
what are the key differences that determine the balance of inflammation and homeostasis?
- TGFbeta
- IL-10
- IFNy
-IL-17
-TNFalpha
important points to remember:
- barrier organs are an immunological battlefield
- communication between epithelial and immune cells is critical
- mucosal immune systems are composed of secondary, tertiary lymphoid organs as well as tissue
- the microbiome contributes to the immune response and tissue homeostasis
- key cytokines determine the balance between homeostasis (TGFbeta, IL-10) and inflammatory responses (IL17, TNFalpha, IFNy)
what are the distinct sections that the gut is organized in?
stomach, small intestine, large intestine
what is the pH a strong determinant of?
the species of bacteria we can find in each section
where is microbial abundance the highest?
further down the intestinal tract, i.e., the large intestine
what are the gut epithelial cells and what is their function?
- enterocytes: absorption
- goblet cells: mucus production
- microfold cells: transcytosis of antigen
- paneth cells: secretion (AMPS)
- Tuft cells: sensor cells
- Intraepithelial lymphocytes: rapid antigen-specific responses
what are the first lines of defense
- mucus barrier
- epithelial barrier
- IgA secretion
what are IgA? what do they do?
a unique set of antibodies produced by B cells, that are released into the mucosal layer via transcytosis.
They block pathogen receptors or virulence factors and agglutinate pathogens of virulence factors to trap them (immune exclusion)
what are two ways to induce IgA production?
- T cell-dependent IgA induction
- T cell-independent IgA induction
4 main functions of IgA:
- secreted IgA on the gut surface can bind and neutralize pathogens and toxins
- able to bind and neutralize antigens internalized in endosomes
- IgA can export toxins and pathogens from the lamina propria while being secreted
- binding of IgA to Dectin-1 on M cell allows transport of antigen to DC-SIGN+ dendritic cell
what is the importance of the regulatory T cell?
it is the heart of a complex system
traits of the regulatory T cell
- subset of CD4+ T cells
- Two origins: Thymus vs Periphery
- Master transcription factor: Foxp3
- general functions:
1. peripheral tolerance
2. tissue repair mechanisms
3. establishment of long-term memory response
what are T helper type 17 cells?
- differentiated CD4+ T cell
- express the transcription factor RORyT
- releases inflammatory cytokines (IL17A, IL17F, IL21) tissue repair cytokines (IL22)
how do firmicutes communicate with the immune system?
release short chain fatty acids which
1. directly favor Treg cell generation
2. promote IL-22 production by Th17 cells
how do bacteroides communicate with the immune system?
release polysaccharide which
1. directly favor Treg cell generation
2. suppress IL-17 production by Th17 cells
what are the therapies that target the altered microbiota in the gut?
- pre and probiotics
- transfaunation
- helminth therapy
how is tolerance to the intestinal commensal microbiome achieved?
through interactions between the microbiome, epithelial cells, and immune cells in the lamina propria
what do antigen-presenting cells in the healthy intestine do?
travel to secondary lymphoid tissue and polarize naive T cells to the T lineage
IgA-producing B cells are generated in both …
T-cell dependent and T-cell independent manners
what is the two phase response to an infection?
the induction phase and the effector phase
what is the induction phase?
recognizing the danger. this phase is engaged when the system recognizes that there is a danger that cannot be controlled by physical mechanisms. it recognizes this via pattern recognition receptors
what are the types of PRR receptors involved in sensing an infection?
- toll like receptors
- NOD-like receptors
- RIG-I like receptors
what is the effector phase?
dealing with the danger. This phase is characterized by the generation of antigen-specific T and B cells. It is a strong inflammatory phase, i.e., recruitment of neutrophils, eosinophils, macrophages and inflammatory dendritic cells. the goal is to expel the pathogen
what is the significance of salmonella typhimurium?
- bypass the microbiome and mucus
- survive the effect of AMPs and IgA
- penetrates M cells and then macrophages- survives the low pH and grows on sialic acid
what is required to control s. typhimurium?
type 1 immune responses that involves:
- Th1 T cells that produce IFNy
- cytotoxic T cells that target the infected cells
- specialized innate cells
- alarmins like IL-1beta and IL-18
what are the specialized innate cells in type 2 immune responses?
ILC2, eosinophils, mast cells
what are unique immune cells of the respiratory tract?
- alveolar macrophages
- club cells (clara cells)
what are unique aspects of the respiratory tract immune system?
- microbiome decreases as you get to the lower respiratory tract
- gas exchange required RAPID control of pathogens
- strong homeostatic pressure:
1. amphiregulin
2. TGFbeta
important thing to remember about the skin barrier:
it is NOT a mucosal barrier, i.e., not a part of MALT
what are the immune cells of the skin
- langerhans cells (type of DC)
- γδ T-cells
- resident memory CD8+ T-cells
- Tissue localized T-reg cells
what do langerhans cells do
patrol the epidermis (TLRs) and present the antigen to T and B cells
what are γδ cells?
- Tcells that did not mature into αβ T cells
- quick responders to pathogen antigens: IL-17
- not very specific
what do resident memory CD8+ T cells do?
specific recognition, are quick responders
what do resident memory CD8+ T cells do?
specific recognition, quick responders
what are tissue localized T-reg cells responsible for
suppression
the mucosal immune response is involved in what two phases?
induction and effector phase
what do type 1 immune responses target?
intracellular pathogens
what do type 2 immune responses target?
helminths, but are involved in airway allergy
where are specialized immune cells found in?
distinct mucosal organs
the skin is a …
unique barrier organ; its physical, chemical and immunological attributes are unique
autoimmunity =
breakdown of tolerance to self
where does central tolerance happen?
in the primary lymphoid organs
where are autoreactive B- and T- cells killed?
in the bone marrow and thymus by apoptosis
what is the “hit and run” theory?
- high affinity, transient –> tolerance
- high affinity, sustained –> deletion
what are ways central tolerance is done?
- apoptosis of autoreactive cells
- clonal deletion
- hit and run theory
- receptor editing
what is peripheral tolerance?
deletion, anergy, or induction of regulatory function in T cells recognizing self antigen
what do immunogens lead to?
immune activation
what do tolergens lead to?
tolerance
what promotes tolerance?
- high doses of antigen
- long term persistence of antigen
- oral introduction
- low levels of co-stimulation
- presentation by immature of unactivated APCs
what are traits of T-reg?
- immunomodulatory
- express FoxP3 (regulatory self antigens)
- CTLA-4 inhibits activation
- CD25
- releases IL10 and TGF-beta cytokines
- kill effector T cells
- starve effector T cells
what do B-reg cells do?
- express high levels of IL-10
- suppress inflammatory cascades associated with IL-1
- mouse models of MS/RA
when B cells are incapable of secreting IL-10
disease is worsened
what happens in autoimmunity?
happens when immune response target self-antigens
- can be organ specific or systemic
how can autoimmunity begin?
- autoreactive lymphocytes escape clonal deletion
- failure of peripheral tolerance
- cryptic antigens
- molecular mimicry
- super antigens
- bystander activation
who is more susceptible to autoimmune diseases? why?
cis women
- mount more vigorous immune responses
- higher levels of circulating CD4+ T cells, immune cell activation
- higher rate of transplanted graft rejection
- estrogens are associated with enhanced immunity
type 1 diabetes:
- organ specific
- target: beta cells in pancreas
- treatment: daily insulin
what is systemic lupus erythematosus?
- systemic autoimmune disorder
- more frequent in cis women; African American and Hispanic
- auto-antibodies target common cellular components
- symptoms: fever, weakness, arthritis, kidney dysfunction
what is multiple sclerosis?
- neurologic disability more common in Western countries
- autoreactive CD4+ T cells, th17 cells and IL17
- target: myelin sheath of nerve fibers
- commonly manifests as “relapsing and remitting”
- has genetic and environmental associations; infection with Epstein-Barr virus, diet, smoking, obesity, exposure to sunlight
what is rheumatoid arthritis (RA)?
- chronic inflammation of the joints
- antibodies react with citrullinated protein antigens and rheumatoid factors
- RFs (generally IgM) are specific for Fc region of IgG
- RF + IgG deposit at joints and lead to complement activation
- associated with gingivitis and smoking
what are the treatments for rheumatoid arthritis?
- no cures
-range from general immune suppression to targeted immunotherapy
-broad spectrum
-corticosteroids, cyclophosphamide, methotrexate
-removal of organs or compounds - specific treatments: Rituximab, block inflammation, statins
what are the kinds of transplantation?
- autograft (self-tissue to self)
- isograft (between genetically identical individuals)
- allograft (between genetically different, same species)
- xenograft (between different species)
what organ is the transplanted most commonly?
kidney
- we can survive with only one
- simple surgical procedure
- longer lifespan outside of body
what is the significance of bone marrow and hematopoietic stem cell transplants
- treats hematologic diseases such as leukemia, lymphoma, and severe combined immunodeficiency
what is the requirement in finding a match for a bone marrow or HSC transplant?
difficulty finding matches - needs the same MHC alleles
what is a potential outcome of BM or HSC transplants?
graft-versus-host disease (GvHD) - immunocompetent donor cells can attack recipient
what is histocompatibility?
having the same set of alleles of a set of genes in human leukocyte antigens or MHCs. requires blood group matching
where are blood group antigens found?
on RBCs, epithelial cells, and endothelial cells
most transplants are…
between individuals with matching blood types
what is hyperacute rejection?
- when grafted tissue does not get vascularized
- happens very quick
- antibodies against A or B antigens may arise from nature/gut commensals
- antibodies against MHc may be from previous blood transfusion, past pregnancy, infectious agents, or previous transplant
what is acute rejection?
- occurs in two stages: sensitization and effector
- direct recognition: T cells recognize unprocessed antigens on the graft APC
- indirect recognition: recipient APC uptakes and processes draft antigens and present and activate recipient T cells
- often treatable/reversible
chronic rejection:
- develops months or years later
- include both humoral and cell mediated responses
- immunosuppressive drugs work in the short-term
total lymphoid irradiation:
- X rays kill lymphocytes
- used before BM or HSC transplants
- multiple X-rays to thymus, spleen, and lymph nodes
- BM is not irradiated so stem cells replenish the recipient with new lymphocytes
- can also be used to treat GvHD
what is given to suppress one’s immune system?
- Azathioprine
- Cyclophosphamide
- Methotrexate
- usually given in combination with corticosteroids
what is the problem with giving mediation to suppress one’s immune system?
causes total immune suppression
what are the fungal metabolites, and what do they do?
- cyclosporin A (CsA), FK506 (tacrolimus), rapamycin
- block activation and proliferation of resting T cells
- do not affect other leukocytes
- CsA toxicity to the kidney
- FK506 and rapamycin can be given in lower doses with fewer side effects
- problem: All T cells are inhibited
specific immunosuppression:
- monoclonal antibodies: can target cells, cytokines, or costimulatory signals
- block CD80/86 using mAbs; induces anergy in T cells and approved by FDA for adult kidney transplants
exceptions of immunosuppressive drugs:
sometimes allografts can be accepted without immunosuppressive drugs - tissue that lack alloantigens (cartilage, heart valves)
immunologically privileged sites …
are less likely to be rejected, less lymphatic vessels, and sometimes blood vessels
