Flashcards in Immunity to infection 1+2 Deck (69):
What are the general features of microbial immunity?
There is innate immunity which is the first line of defence with immediate action this is not enhanced by previous exposure and functions based on pattern recognition and uses features such as complement, anti microbial peptides and NK cells
Adaptive immunity however will only start 4-7 days after infection and involves the response of antigen specific lymphocytes and has immunological memory
What are the specific interactions which may occur between a bacteria and a phagocyte?
There may be interactions between lectins and oligosaccharides on the surface of either of the cells
Alternatively several compounds may be deposited on the bacteria and recognized by the phagocyte such as antibodies (recognized by an Fc receptor), Mannose-Binding lectin (recognized by C1qR), iC3b (recognized by both p150,95 and CR3) and C3b (recognized by CR1)
What is the key difference between immunity to extracellular gram negative and gram positive bacteria?
Gram positive bacteria are not as effectively killed by complement
What is the early immune response to bacteria?
There is increased vascular permeability, Chemotaxis, activation of phagocytes and activation of the endothelium so that phagocytes can better and adhere to it
How does the increased vascular permeability seen in the early immune response to bacteria occur?
The bacteria leads to the activation of complement which can lead to the activation of Mast cells which produce histamine leading to increased vascular permeability
How does the chemotaxis seen in the early immune response to bacteria occur?
Bacteria can activate complement which will result in the production of anaphylotoxins to induce chemotaxis as well as activate mast cells to produce IL-8 to mediate chemotaxis
Bacterial components are also capable of activating macrophages to produce IL-8
How are phagocytes activated in the initial immune response to bacteria?
Bacteria activate complement which will result in the production of components which will activate phagocytes
Bacteria may also activate NK cells to produce IFN-gamma which activates phagocytes
Bacterial components may activate macrophages to produce IL-12 and TNF which can activate NK cells to produce IFN-gamma activating phagocytes
How do phagocytes have increased adhesion and endothelial cells become activated in the early immune response to bacteria?
Bacterial components activate macrophages to produce Il-1 and TNF-alpha cause increased adhesion of phagocytes as well as activating endothelium which itself also causes increased adhesion of phagocytes
What is the acute phase response seen in the early immune response to bacterial infection?
Bacterial components activate macrophages to produce IL-1, IL-6 and TNF-alpha (IL-6 being the major player here) which induce the liver to produce acute phase proteins including mannose-binding lectin, surfactants SP-A andSP-D as well as C-reactive protein
How can the immune response against pathogens lead to shock and death?
Certain bacterial compounds like LPS can activate macrophages to produce IL-1, IL-6, TNFalpha and other endogenous pyrogens which can lead to endotoxic shock
Alternatvely superantigens can non-discriminately activate T cell subpopulations leading to production of IL-1, TNFalpha from macrophages and IL-2 from the T cell inducing toxic shock
What are the features of endotoxic shock?
There is a significant change in vascular permeability, loss of fluid into the tissue and a fall in blood pressure
The symptoms include fever, circulatory collapse, diffuse intravascular coagulation, haemorrhagic necrosis and multiple organ failure
How cod bacteria avoid complement mediated damage?
They may have an outer capsule or coat which prevents complement activation
Long side chains such as the O antigen on bacterial LPS may prevent the binding of Cb3 to the complement receptor
Surface structures on the microbe divert attachment of lytic complex to the membrane
Membrane bound enzyme degrades fixed complement or causes it to be shed (such as Pseudomonas elastase which cleaves C1q and IgG)
There is a resistant outer membrane (containing large amounts of sialic acid)
Secretion of decoy proteins that bind complement (like SIC protein of S. Pyogenes)
What is the unique feature of the S. Pyogenes capsule?
It is made of hyaluronic acid which is a host protein and can therefore facilitate immune evasion
What is the oxygen dependent mechanism of phagocytosis?
Inside the phagosome a respiratory burst occurs this involves reactive oxygen intermediates such as the hydroxyl free radical, super oxide and peroxide which may directly kill the pathogen through the peroxidase independent pathway or myeloperoxidase/catalase can also act on peroxide to produce hypochlorous acid which may kill the pathogen in the peroxidase dependent pathway
What is the nitric oxide pathway of bacteria killing?
IFN-gamma can activate inducible nitric oxide synthase resulting in Nitric oxide synthase with its tetrahydrobiopterin cofactor being able to use O2 and L-arginine to produce citrulline and the toxic Nitric oxide
This process may be enhanced by the actions of TNF and crosslinking of CD23
What are the escape mechanisms bacteria have from phagolysis?
They may inhibit chemotaxis through secretion of repellents or toxins preventing the phagocyte from taking up the bacteria
They may also have capsules or outer coats which prevent attachement and uptake by phagocytes
Release of factors which block the triggering of killing mechanisms such as blocking lysosome fusion, inhibiting the proton pump or the release of catalase
There may be blocking of the IFNgamma signal through compounds such as lipoarabinomannan
There may be a resistant outer coat which scavenges free radicals like phenolic glycoprotein
What is toxic shock syndrome?
This is something which may occur as a result of S. Pyogenes or S. Aureus infection where superantigens act of case hypotension, fever, rash, vomitnng and shock
What is Whooping cough?
This is something which may occur as a result of Bordetella pertussis, where pertussis toxins act to cause ADP-Ribosylation of G-proteins and induce lymphoproliferation
What is tetanus?
This is something which may occur as a result of Clostridium tetani which produces tetanus toxin which blocks inhibitory neuron action and induces muscle cramps
What is diphtheria?
This is something which may occur as a result of Corneybacteria diphtheria which produces diphtheria toxin which inhibits protein synthesis leading to epithelial cell damage
What is cholera?
This is something which may occur as a result of vibrio cholera which produces cholera toxin which activates adenylate cyclase leading to an increase in cAMP
What is Botulism?
This is something which may occur as a result of clostridium botulinum which produces botulinum toxin which blocks the release of acetylcholine triggering paralysis
What is Anthrax?
This is something which may occur as a result of Bacillus anthracis which produces anthrax toxin which increases vascular permeability leading to edema and haemorrhage
How can the immune system neutralise bacterial toxins?
Through high affinity IgG and IgA which prevents the toxin from binding to its receptor
What is the role of antibodies in microbial immunity?
Antibodies to fimbriae, lipoteichoic acid and some capsules and adhesins can block bacterial attachement
Antibodies can trigger complement mediated damage to the bacteria or block transport mechanisms and receptors preventing bacterial proliferation
Antibodies to capsules can lead to opsonisation via Fc and C3 receptors or they may neutralise immune repleelents prevent the bacterias ability to avoid phagocytosis
Antibodies to toxins can prevent bacterial toxin mediated damage
Antibodies can neutralise spreading factoes like hyaluronidase preventing the bacteria from becoming invasive
How do microbes counteract the activity of antibodies?
They have rapid cell division
Host like coat (Hyaluronic acid or fibrin deposits)
Soluble antigen release as a decoys
Antibody specific proteases
What is antigenic variation?
Due to genetic or allelic variation microorganisms are often able to change epitopes in prtoeins or carbohydrates
What is the difference between Th1 and Th2 responses to infection?
Th1 cells drive cell mediated immunity with the production of TNF and IFNgamma which lead to macrophage activation (as well as IL-2 production to drive more Th1 production) Th1 cells also respond to IL-12 from the macrophages
Th2 cells however drive humoral immunity with production of IL-4 prevent macrophage activation by IFN-gamma and IL-10 preventing Th1 proliferation
How do Th1 and Th2 response differ in the host response to mycobacterium leprae?
If a Th1 response predominates then the tuberculoid form of the disease will develop as this will induce a vigorous host cellular response with many immune cells in the lesions, there may also be tissue damage as a result of type IV hypersensitivity, there will only be a few bacteria visible microscopically and disease progress is slow with the patient typically surviving
If a Th2 response predominates then the lepromatous form of the disease will predominate with humoral response, there will be an adequate antibody response but this will be unable to access the intracellular bacteria, this results in there being many bacteria in the lesions, the patients being highly infectious along with gross tissue destruction and the disease typically being fatal
What are the features of parasites?
Most parasites are host specific due to receptor specificity
Many parasites have complicated life cycles which may involve more than one host
Many protozoa rely on an insect vector
There is a greater variety and quantity of antigens compared to bacteria
Antigenic variation is common
How does antigenic variation occur in parasites?
There is programmed DNA rearrangements as seen in Trypanosoma spp. Where there are over 100 inactive VSGs and only one active one and then gene conversion will occur to change this active one facilitating immune evasion
What are the features of infections with parasites?
Certain antigens are only expressed at particular stages of development
Host resistance to the parasite may be genetically determined (for example certain HLA-antigens correlate with protection against malaria or the lack of the duffy antigen on erythrogytes protects from malaria
Many parasitic infections are chronic where they are controlled by the immune system but not eradicated
What are some examples of protozoan parasites which cause disease?
Plasmodium spp. Which cause malaria
Toxoplasma gondii which cause Toxoplasmiosis
Leishmania spp. Which causes leishmaniasis and orient boil
Trypanosoma spp. Which cause sleeping disease and chagas disease
What is leishmaniasis?
This is a disease caused by intracellular protozoa which reside in macrophages transmitted by a sandfly vector and causes damage to the spleen and liver
There are about 500,000 deaths a year due to the visceral form of this disease
What is the difference between the Th1 and Th2 response to leishmaniasis?
A Th1 predominating response will result in cutaneous leishmaniasis or the Baghdad boil where there is a vigorous host cellular response with many immune cells in the lesions and limited disease
A Th2 predominateing response however will result in the visceral form of the disease or Kala-azar where there is a defect in cell mediated immunity and instead there is a humoral response which, while adequate, is not capable of reaching the intracellular populations of the parasite resulting in there being many parasites in the lesions and disseminated disease
What is malaria?
This is a disease found mostly in central Africa which is transmitted by the anopheles mosquito
It results in about 1-1.5 million deaths/year
There is some natural protection against this disease through sickle cell disease r other RBC abonormalities
What is the difference between the Th1 and Th2 response to malaria?
Different life cycle stages of the parasite require differently driven response
The initial stage where sporozoites are present in the blood requires a Th2 mediated antibody response
The next stage where there are tissue schizonts in liver tissue requires a Th1 driven response controlled by cytotoxic T cells, TNF and IL-1
The stage after that has merozoites in the blood and requires a Th1 driven humoral response
The final stage is the asexual erythrocyte stage which requires both a Th1 and a Th2 response where there is antibody production as well as ROI, RNI and TNF production
What are the parasitic worms?
Nematodes or round worms such as hookworm filarial, whipworm and trichinella spp.
Trematodes or flukes such as Fasciola spp. And Schistomona spp.
Cestodes or tapeworms such as taenia spp
What are the features of schistosoma mansoni?
Larvae are released from the water snail and penetrate the skin they then migrate through the blood and lung to the hepatic portal vein leading to intestinal schistomiasis or snail fever
What are the features of schistosoma haematobium (bladder fluke) infection?
Larvae are released from water snails and penetrate the skin where they migrate to the veins of the bladder and cause urinary schistosomiasis
What is the immune response to schistosome larvae?
The parasite antigen is recognised by antibodies which then go on to activate mast cells which produce the toxic histamine and herapin
The mast cell will also go on to cause Th2 cells to produce IL-4 which mediates a class switch in B cells to produce IgE and IgG
Th2 cells may also produce IL-5 which activates eosinophils
Th1 cells produce IFN-gamma which activates macrophages which damage the parasite directly and produce TNFalpha which can cause platelet mediated damage, activate eosinophils and neutrophils
What is general immune response to parasitic worms?
This is mainly Th2 regulated
Mast cells and eosinophils play critical roles
Some parasitic antigens act as B cell mitogens resulting in non-specific Ig production
Parasite is usually too large for phagocytosis
Antibodies (mainly IgE and IgG) bind to the parasite to sensitize it
Macrophages, neutrophils and eosinophils bind to the parasite via an antibody Fc receptor
This leads to the release of reactive oxygen intermediates, NO and major basic protein which are toxic to the parasite
There is antibodie dependent cell mediated cytotoxicity
Mast cells produce inflammatory mediators such as histamine and heparin which are toxic for the parasite
What are viruses?
These are obligate intracellular parasites which depend on host cell metabolism
They have high structural and genetic diversity due to a high mutation rate
They are host specific with infection depending on specific receptors on the host cell
What are the innate and adaptive immune responses to viruses?
The innate response is where IFN stimulates inhibition of viral relication
NK cells are cytotoxic for virally infected cells
Complement can damage virion envelope
The adaptive immune response is where antibodies limit viral spread an reinfection and CD8 T cells destroy virally infected cells
What is the role of cytokines in viral infection?
A virally infected cell will secrete IFN alpha and beta which induces resistance in neighbouring cells which upregulate TAP, MHC I and LMP
These type 1 interferons will also activate NK cells which will kill cells which have low MHC-1 as this is a sign of viral infection, perform antibody dependent cell killing as well as produce IFNgamma which is a type 2 interferon which will induce host cell resistance and induce an adaptive response involving Th1 cells
What are the host defences against viral infection?
Viral entry may be blocked by IgA/IgG neutralisation
NK cells may kill infected cells
IFN can inhibit the infection of uninfected cells
Infected cells may be opsonised vie Fcgamma and complement receptors on macrophages
Antibody-dependent-cell-mediated-cytotoxicity may kill infected cells
What is an immunodeficiency disease?
This results from an absence or failure of the normal function of one or more elements of the immune system
What is the difference between specific and non-specific immunodeficiency?
Specific immunodeficiency involves B and T cells and includes conditions like severe combined immunodeficiency and adenosine deanimase deficiency
Non-specific immunodeficiency involves the innate immune system such as complement and phagocytes
What is the difference between primary and secondary immunodeficiency?
Primary immunodeficiency is a result of an intrinsic defect which is most likely genetically determined
Secondary immunodeficiency is due to acquired defects such as drugs, malnutrition or HIV infection
How was acquired immunodeficiency syndrome discovered?
This was first reported in july 1981 with karposi’s sarcoma and pneumocytosis Carinii pneumonia among homosexual men in New York City and California
There was a noted susceptibility to infection with opportunistic pathogens or occurance of an aggressive form of Karposi’s sarcoma or B cell lymphoma
The causative agent of this was identified in 1983 in Europe and the USA and named Human T cell lymphotrophic virus III by Robet Gallo and Lymphadenpathy associated virus by Luc Montagnier
This was later renamed HIV-1
In 2010 an estimated 34 million people were infected
About 99% of all infections occur in developing countries (68% in sub-Saharan Africa)
About 30 million people have died of AIDs since 1981
What are the features of the HIV virus?
There are two major types, HIV-1 (more virulent) and HIV2 which is endemic in West Africa
Its host cells are CD4 T cells, dendritic cells and macrophages
It is from the family of retroviruses and the group lentiviruses
It is transmitted via sexual intercourse, contaminated needles, use of infected blood or blood products and breast feeding of an infected mother
What is the cellular tropism of HIV?
There is a lymphocyte-tropic virus which uses CXCR4 and needs high levels of CD4 on T cells
There is also a macrophage tropic virus which uses CCR5 as a coreceptor and requires only low levels of CD4
CCR5 is expressed on Dendritic cells, macrophages and activated T cells
What is cellular tropism?
The ability to enter a particular cell type based on the expression specific host receptors?
What is the typical course of an untreated HIV infection?
The primary acute infection is often asymptomatic or causes flu like (mono-nucleosis-like) illness
The HIV will first infect a DC which will carry it to the lymph node, T cells clustered with DC bcome highly activated due to vigorous HIV replication
A lack of protective response results in viremia
There is a drop in CD4 T cells and activation of CD8 T cells
The CD4T cell number rebounds leading to the clinical latency or asymptomatic period
There is production of antibodies or seroconversion (important for diagnostics), the virus remains replicating in the lymphoid tissue however the patient feels well
There is a gradual decline of CD4 T cells resulting in the symptomatic phase of the disease where lymphadenopathy occurs along with fever, sweating, weight loss and AIDs
What is the immune response to HIV?
Cytotoxic CD8 T cells and Th1 cells are responsible for the initial decline of the virus after its initial infection
HIV generates a humoral response which will contain the virus but not eliminate it
There is major reservoir of HIV in lymphoid tissue with a loss of CD4 cells occurring by direct viral killing, increased susceptibility to apoptosis, killing by CD8 cytotoxic T cells that recognize viral peptides
When CD4 cells drop below critical number then cell mediated immunity is lost and opportunistic infections develop
How does HIV escape the immune system?
Neutralising antibodies can control HIV particles in the blood but cannot eliminate the virus altogether, the high replication and mutation rates of the virus result in the development of quasi species which develop into escape mutants
There is antigenic variation of the immunogenic surface proteins gp41 and gp120 which can develop new epitopes not recognized by CTLs
Provirus may hide inside the cell on the host chromosome in latent infections
HIV can interfere with the synthesis of MHC-1
What are the potential sites of action of HIV therapeutics?
Reverse transcriptase inhibitors
How can reverse transcriptase be targetted for HIV therapy?
The use of nucleoside analogues like azido-thymidine (AZT, Zidovudine and Retrovir)
What is HAART?
Highly active antiretroviral therapy where a protease inhibitor is combined with 2 or more RT inhibitors
What is the Influenza A virus?
This is a virus from the orthomyxoviridae famile with a genome made of 8 single stranded, negative sense RNA segments
The virus has two key surface proteins, Hemagglutinin which binds to sialic acid-containing receptors on epithelial cells of host and neuraminidase which cleaves sialic acid at the end of the virus life cycle which allows mature virions to be released
What are the innate and adaptive immune responses to influenza A infections?
The innate response involves type I interferons which provide virus resistance , the viral replication/cell lysis leads to production of IL-1, IL-6, IL-8, TNF, IFNgamma it is this response which leads to disease symptoms
The adaptive immune response occurs with HA and NA specific CD8 T cells in the lung though efficient clearance also requires CD4 T cells there is also production of IgA and IgG for neutralisation of HA
What are the influenza A subtypes?
There are 16 non-overlapping subtypes of HA but only 3 are associated with human disease (H1, H2 and H3)
There are 9 non-overlapping subtypes of NA but only 2 are associated with human disease (N1, N2)
All subtypes are found in aquatic birds as these are the natural reservoir for Influenza A virus
What is the role of receptor specificity in Influenza subtypes?
Human HA types can bind 2-6 sialic acid
Avian HA types bind 2-3 sialic acid
Pig HA types can bind both
What are the mechanisms which generate antigenic variation in influenza virus?
There can be antigenic drift due to the high error rate of the replication enzymes of the virus
Alternatively there may be antigenic shift when two distinct influenza viruses infect the same host cell and their genome segments get mixed up during replication creating dramatic changes in viral make up
How do influenza pandemic typically develop?
This can develop with the emergence of a new virus with high transmission capability that harbours a novel HA that has not circulated for decades
This typically will occur following an antigenic shift where there is genetic reassortment between human and avian viruses in pigs
What are recent examples of antigenic shift?
H5N1 bird flu this is highly pathogenic but has low transmission as H5 does not usually bind human receptors however if H5N1 rearranged in pigs with an HA that can bind human receptors then this could cause a pandemic
H1N1 or swine flu is a highly virulent strain but it is not very pathogenic
What have been the pandemics caused by influenza?
1918 with the Spanish flu where there was 40-50 million deaths worldwide caused by the H1N1 strain
1957 there was the Asian flu caused by a H2N2 strain after H2 was replacement with an avian strain
1968 there was hong kong flu caused by H3N2 strain with H3 from an avian strain
In 1977 there was the Russian flu caused by H1N1
What are the features of H5N1?
This is highly pathogenic but only weakly transmissible to humans however a pandemic is possible if the strain mutates or rearranges with a human strain