Immunology Chapter 18 - Immunodeficiency Diseases
Antibody protein therapeutics are
Antibody protein therapeutics are expensive, but passive transfer of bNAbs may complement antiretroviral drugs as part of the arsenal against HIV/AIDS. With that in mind, a tri-specific antibody was designed. the bNAbs might be able to be an addition method used in tritheropys one antibody that has three different env binding sites
what is autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED)?
In addition to recognizing and eliminating foreign antigens, the adaptive immune system must learn to recognize self MHC proteins and to be proactive in suppressing reactions to self antigens in the host. These key processes are carried out by the induction of tolerance in the thymus and by the surveillance activities of regulatory T cells (TREG cells). Thus, some immunodeficiency disorders the defects lead to immune dysregulation that results in some autoimmunity. Individuals with a defect in the autoimmune regulatory gene AIRE suffer from a disease called autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). Proper expression of peripheral tissue proteins in the thymus facilitates the negative selection of autoreactive T cells before they can exit into the circulation and the generation of thymic TREG cells. It appears that depressed expression of AIRE in these individuals results in reduced levels of tissue-specific antigens in medullary thymic epithelial cells, allowing the escape of autoreactive T cells into the periphery, where they precipitate organ-specific autoimmunity. Patients with APECED experience disruption of endocrine function, including hypoadrenalism, hypoparathyroidism, and hypothyroidism, along with chronic candidiasis. Autoimmune responses against antigens present in these endocrine organs, as well as the adrenal cortex, gonads, and pancreatic beta cells, are observed in these individuals. Although autoantibodies to these tissues are also observed, these may result from the tissue destruction mediated by pathogenic T cells. all of the primary immunodeficiencies we have seen before have really been linked to an inability of the immune system to recognize a pathogen and stop an infection. But if you think about it our immune system does not just recognize what is nonself and destroy it, it also recognizes self so that it does not attack our own cells. Well it turns out that there are some immunodeciencys that involve molecules that are apart of central tolerance and in particaular some individuals have a disease called APECED which is linked to the absence or malfunction of the AIRE protein. (if you remem the processes of T cell development in the thymus. once we have a t cell that has a TCR, it going through neg selection and then positive selection. From the cells that survive these selections, some will express CD4 some will express CD8. but these cells are subjected to a second round of negative selection which involves AIRE. AIRE is pretty much there to increase the expression of non-thymic proteins on the surface of APCs and in doing so it is favoring the selection of T cells that have less autoreactivity bc it is expressing proteins/antigens that are not normally found in the thymus therefore it is helping those t cells learn self and nonself based on binding to novel proteins.) Well a defect in the protein AIRE therefore, results in an increase in autoimmunity. In addition, patients that have a defect in AIRE are also effected by candidiasis which is a disease that involves recurrent infection by the fungal cell canidia. Tregs are selected in the medulla of the thymus that bind with high affinity for self MHC complexes but not to high. Tregs are selected to promote tolerance. Well in the absence of AIRE those Tregs my not form normally and there will be an issue with the tolerance mechisums in the GI tracked. (bc in the GI track tolerance depends on our expression of Ig anitbodies and expression of Tregs to basically provide an absent immune response to those commensal bacteria. therefore in the Tregs we are going have an increased response again those commensal microbes which will lead to their distruction which will lead to disbalance in our microbota which then allows for an increase in bacterial and fungal infections considering commenal bacteria usually crowed out the bad bacteria and fungus. This is why patients with a defect in AIRE have an increased infection of candidasis.
what is the life cycle of the HIV virus?
(a) first during infection, the virus will bind to either CD4 through its protein gp120 (but that in it of itself is not enough for entry of the virus, its rather the binding of gp120 to either CXCR4 or CCR5 that causes the virus to fuse with its target membrane) but once the virus fuses with the membrane we have the release of the viral particles inside the cytoplasm of the cell. this then leads to the release of the viral RNA genome, reverse transcriptase is going to transform the single strand of RNA into RNA cDNA hybrid and then dsDNA which will be integrated into the host genome (this integration is one of the targets of immunotherapys) (b) now once the virus is activated, the integrated cDNA is transformed into mRNA which can express different proteins and these proteins are used to reassemble a viral particle which can then bud off of the host cell and infect other cells Bc pg120 binds to CD4 this virus is going to target helper T cells, hence the immunodeficiency because if the helper t cells are not working efficiently then we can have a case of server combined immunodeficiency because helper t cells are not working which means that the activation of CD8 cytotoxic t cells is going to be impaired and also the activation of t dependent b cells is going to be impaired. (therefore we are almost talking about a complete breakdown of the adaptive immune response in the response to an HIV infection)
The first part of this chapter describes the most common primary immunodeficiency diseases, examines progress in identifying new defects that can lead to these types of disorders, and considers approaches to their study and treatment. The rest of the chapter describes acquired immunodeficiency in the context of HIV/AIDS, including the current status of therapeutic and prevention strategies for combating this disorder, which is fatal if untreated.
1.Primary immunodeficiencies - diseases linked to a defect in one particular gene which prevents the development of one part of the immune system (for instance there are no t cells available in one particular individual) 2.Secondary immunodeficiencies - these individuals do not have any defects in their immune system but for some reason or another they have acquired an immunodeficiency (for ex. HIV/AIDS) immunodeficiencies are linked to an inability of the immune system to do its jobs properly and recognizing non-self.
what are combined immunodeficiencies? what are severe combined immunodeficiency?
Among the most severe forms of inherited immunodeficiency are a group of disorders termed combined immunodeficiencies (CIDs): diseases resulting from an absence of T cells or significantly impaired T-cell function, combined with some disruption of antibody responses. Severe combined immunodeficiency (SCID) is the most extreme form of CID and arises from a lack of functional T cells (which also manifests as the absence of T cell-dependent B-cell antibody responses). Some SCID genetic defects prevent the formation of both B and T cells, such as defects in hematopoiesis, lymphoid development, and V(D)J gene rearrangements in both B and T cells. Generally target early T-cell development steps or required stem cells: •Defective differentiation of myeloid and lymphoid lineages from HSCs •Defective cytokine signaling in T-cell progenitors •Defects in purine metabolism (toxicity and/or death) •Rearrangement defects caused by RAG1, RAG2, or other proteins involved in gene rearrangement •Signaling defects of pre-TCR or TCR CIDs are diseases that result from an absence or impaired T-cell function. (remember that if T cell function is impaired B cell function is also impaired bc helper t cells are the ones that are helping B cells develop and antibody against a protein antigen. Also in B cells we have T cell dependent B cell responses which involve somatic hypermutation and class switching and we also have T cell independent B cell responses) So if there are no T cells there are really no good antibodies around. from the HSC we can become a CLP which can become a NK cells, T cell progenitor, or B cell progenitor. In SCID there are no T cells at all therefore there are also no T cell dependent B cell responses as well. SO what are some of the defects that might cause SCID? Anything that prevents the differentiation of the CLP into a T cell progenitor or anything that prevents the differentiation of a t cell progenitor into a t cell. if there are defects in the RAG1 or RAG2 we will not be able to form a normal t cell progenitor or t cell receptor
what are the steps for stimulating production of broadly neutralizing antibodies to the HIV-1?
An immunization approach for stimulating production of broadly neutralizing antibodies to the HIV-1 Env spike is shown below. Step 1: Broadly neutralizing antibodies from HIV-infected individuals are isolated from memory B cells and sequenced. Step 2: The phylogenetic relationships of the antibodies are established, allowing identification of the probable unmutated (germline) common ancestor (UCA) and intermediate antibodies (IA) leading to the bNAbs; some mutated antibodies are non-neutralizing (nonNAbs). Step 3: The UCA and IA antibodies are synthesized and used as templates to develop a series of immunogen Env spike proteins that, through sequential immunizations, will selectively activate B cells with BCRs evolving through somatic hypermutation toward broadly neutralizing activity. step 1: b cells are isolated. these b cells express a number of antibodies - some of which are bNAbs and some that are not. so the stragie is to identify where those bNAbs are sort of they to reverse engineer what the common ansestor was - which is the original antibody made against the antigen. 3. once we find out what the original antibody is that will be the protein that will be injected into the vaccine.
what is chronic granulomatous disease?
Chronic granulomatous disease: Two distinct forms linked to phagosome oxidase (Phox) proteins: •X-linked form (70%) •Autosomal recessive form (30%) Defect in NADPH oxidative pathway used by phagocytes to generate ROS Results in more bacterial/fungal infections and higher degrees of inflammation responses that produce granulomas another group of diseases that effect the innate immune system are chronic granulomatous diseases. (remem that phagocytes such as macrophages express proteins or molecule that are toxic for bacterial species) this is linked to defects in NADPH oxidase which means there will be no production of hypochloroic acid or NO2 which means there will be an impaired destruction of the pathogens that have been phagocytes my those macrophages. So a result of this defect might be an increase in bacterial and fungal infections
what are complement deficiencies?
Complement deficiencies are relatively common and vary in their clinical impact, but are generally associated with increased susceptibility to bacterial infections. Examples include: •C4 defects leading to generalized failure to activate complement •Alternative pathway failure: failure of entire pathways (remember that recent experiments indicate that up to 90% of the deposited C3b molecules are generated via activation of the alternative pathway). complement deficiencies lead to an increase susceptibility to bacteria infections because when it comes to bacteria there are only two possible ways to clear an infection. 1. complement activation due to antibodies binding to the bacteria or because of minose-binding lectin 2. in the case of intracellular bacteria is was basically macrophages. So any defect in complement is therefore an increase in bacteria subseptability to bacteria infections So in the complement there are many possible defects but we are only going to look at two of them. One is a C4 defect - which prevents the activation of complement following the classical or lectin pathway (bc remember in the initiation of the classical or lectin pathway both accumulate on the proteolysis of C4 and the formation of a C3 convertase that results in the deposition of C3b on the cell surface. and then receptors of phagocytes recognize C3b triggering phagocytosis of the pathogen. SO a defect in C4 thus prevents the deposition of C3b in the classical and lectin pathway and hence phagocytosis. furthermore, there may be some defects in the alternative pathway as well. and the absence or failure of the alternative pathway results in a failure of the entire complement pathway (so both the lectin and classical as well) this is bc the activation of complement results from the activation of the classical or lectin pathway but the alternative pathway serves to amplify those pathways
what is tropism? what is the HIV tropism?
During the course of an infection the tropism of the virus particles (i.e., which cells they will infect) often changes. The chemokine receptors CCR5 and CXCR4 serve as the major coreceptors for HIV. CCR5 is expressed by effector memory CD4+ T cells (which give rise to effector T cells after activation), macrophages, brain microglial cells, and dendritic cells, while CXCR4 is expressed on naïve CD4+ T cells and central memory T cells (which proliferate extensively after activation before generating effector T cells). Most of the CD4+ cells in the epithelial layers exposed to virus-containing body fluids during intercourse or infection of infants (the upper GI tract) express the CCR5 coreceptor, it is the R5 viruses that usually are responsible for the initial infection. Now we have to worry about a couple of different things. First off tropism - which is the cells that the virus is going to infect. whats interesting about the HIV tropism is that it has two tropisms. it can CD4 cells that either express CXCR4 or CCR5 (which are two chemokine receptors) CCR5 is expressed on macrophages, DCs, and effector cells (which are APC. and in fact this is how the virus gets inside the host is because it first effect APCs which will become a resorvor for viral particles which can then effect naive t cells the express CXCR4). while CXCR4 is expressed on naive and central memory t cells
what are broadly neutralizing antibodies?
Given the difficulties encountered to design a safe and effective HIV vaccine, a new approach has been undertaken. This novel strategy relies on broadly neutralizing antibodies (bNAbs). Some infected individuals (10% to 50%) develop bNAbs capable of neutralizing many HIV-1 variants, but only a small percentage develop highly potent bNAbs capable of neutralizing most forms of HIV. So, how can a vaccine strategy be designed to induce bNAbs? Screening serum antibodies or memory B cells from infected individuals for reactivity with many HIV strains indicate that these bNAbs recognize six "vulnerable" sites on the envelope (Env) spike, which is a trimer of three gp120/gp41 heterodimers. These antibodies are unusual. For example, some of the antibodies that recognize the gp120 V1V2 regions at the apex of the trimer have long HCDR3 regions of 30 to 39 amino acid residues (compared with more normal lengths of 10 to 15 residues). In addition to the long HCDR3s (generated by unusual VDJ rearrangements) that help some of the antibodies reach through the glycan shield to bind the protein, most bNAbs have undergone extensive somatic hypermutation. Maturation of bNAbs is a long process that usually takes 2 to 4 years after infection. These characteristics present great challenges for the development of immunization protocols that will stimulate the production of bNAbs. since previous attempts to create a vaccine agains HIV have not worked more recently there has been a renewed attempt that takes advantage of bNAbs. it turns out that some infected individuals will develop bNAbs which can neutralize the HIV viruse. but here the problem - HIV can mutate and it can mutate much faster then our immune system can react to it. The mutations usually occur at the level of the gp120/41 protein but some individuals can devope antibodies that can neulize most forms of the virus. NOW if thats true, can we try to deveope a vaccine that would lead to the production of those bNAbs which could be very effience in preventing an HIV infection. when looking at individuals who produced bNAbs they all had something in common - they all recognized up to 6 sites on gp120/41 - therefore there are 6 sites that can be targeted by the antibodies. but those anitbodies are unusual. for instance they have very long CDR3 loops. the real question is can be induce the immune system to create bNAbs?
what is included in the genome HIV? what are the three most important genes?
HIV has a lipid bilayer and two copies of an RNA genome, which contains three structural and six regulatory genes that encode the proteins necessary for infection and propagation in host cells. HIV carries three structural genes (gag, pol, and env) and six regulatory or accessory genes (tat, rev, nef, vif, vpr, and vpu). The gag gene encodes several proteins, including the capsid and matrix, which enclose the viral genome and associated proteins. The pol gene codes for the three main enzymes that are required for the viral life cycle: reverse transcriptase, integrase, and protease. In fact, the protease enzyme is required to process the large Gag and Pol precursor proteins into smaller proteins. The env gene is the source of the surface proteins gp120 and gp41, responsible for attachment of the virus to the CD4+ viral receptor and its coreceptor, either CXCR4 or CCR5 (chemokine receptors). as we mentioned before the genome of HIV-1 is an RNA genome and it is composed of genes. the three most important ones are the gag, pol, and env genes. the other genes are mostly involved in regulation of the viruse The gag gene is encoding the proteins that form the capsid (p24) and the matrix (p17) The envelop env gene involves gp120 and gp41 The pol gene involves four proteins which encode reverse transcriptase so in viral genomes what often happens is that one particular gene is actually the precursor for many different proteins which are cut and processed together by a protease and in fact one of the drugs used in the treatment of AIDS/HIV is a protease inhibitor preventing the processing of the above genes preventing certain proteins from becoming active. we will look at the nef protein p27 which reduces MHC expression and therefore it can be recognized by NK cells. Furthemore, the env protein which encodes for gp41 and gp120 is the protein responsable for the attachment of the virus to its cellular target which goes through the proteins CD4+ (which is expressed on helper t cells), CXCR4, and CCR5 (which are both chemokine receptors)
how does the HIV-1 virus get in?
HIV-1 infection is spread by contact with infected body fluids such as occurs during sex (the most common mode of transmission), direct transfers to the blood such as from using contaminated needles, and from mother to infant during pregnancy, childbirth, or breast-feeding. During sexual practices, free HIV and infected cells in semen and vaginal fluids cross the mucosal epithelium through lesions, tears, or abrasions, by transcytosis of free virus, or by virus binding to extensions of dendritic cells. The virus is then transported to draining lymph nodes, where other cells can be infected. how does the HIV-1 virus get in? HIV infection occurs with either the contact with blood or semen but how does the virus get in? the virus can either enter through transitosis and be picked up by a dendritic cell (a) or it can enter through macrophages that have extended their prosesies passed the epithieum and into the mucosa (d)
What is hyper-IgM syndrome?
Hyper-IgM syndrome: An inherited deficiency in either CD40 ligand (CD40L), which is expressed by T cells, or in CD40, which is expressed by B cells and antigen-presenting cells such as dendritic cells, monocytes, and macrophages, leads to impaired interactions between T cells and cells that are presenting antigen. In the absence of this costimulatory signal B cells cannot mount normal responses to T-dependent antigens, including the formation of germinal centers, somatic hypermutation, the heavy-chain class switching that is necessary for production of IgG, IgA, and IgE antibodies, and the production of memory cells. B-cell responses to T-independent antigens, however, are unaffected, accounting for the presence of IgM antibodies in these patients, which range from normal to abnormally high levels and give the disorder its common name, hyper-IgM (HIM) syndrome. Another group of disease that is associated with CID is called hyper-IgM syndrome. whats important to know is that in this particular disease either CD40L which is the ligand for CD40 or CD40 is absent. Therefore we do not get signal 2 (which is the costimlatory signal) in a T cell dependent B cell. In the absence of signal two the B cell will not be activated and therefore there will not be any synthesis of antibodies against this antigen that is being displayed on the MHC class II protein. What this means is that any type of T cell dependent B cell response will be absence and hence the only B cells that will be present and able to function are the B cells that can secrete antibodies in a T cell independent manner. there are two cells that can do this and they are B1B population and the marginal zone B cell population. these bind and respond to T independent B cell antigens and these antibodies are typically IgMs. therefore in this particular disorder, we only see IgMs and no IgG, IgA, and IgE antibodies bc in the absence of T helper cells there can be NO somatic hypermutation and there can be NO class switching.
how does one get diagnosed with an Immunodeficiency?
Immunodeficiency diseases often are detected early in life, as they may cause recurring infections. Today most newborns in the United States are tested at birth for severe immunodeficiencies by screening blood samples for evidence of T-cell receptor gene rearrangements. there are a number of warning signs and if the immune system is not preforming its function the end result might be increased infections. The type of infections also indicate immunodeficiency Immunodeficiencies can effect the antibodies, cell-medicated immunity, complement, phagocytosis, and even regulatory T cells.
What is X-linked agammaglobulinemia?
Immunodeficiency disorders caused by B-cell defects make up a diverse spectrum of diseases ranging from the complete absence of mature recirculating B cells, plasma cells, and immunoglobulin, to the selective absence of only certain classes of immunoglobulins. Patients with inherited B-cell defects are usually subject to recurrent bacterial infections but display normal immunity to most viral and fungal infections because the T-cell branch of the immune system is largely unaffected. X-linked agammaglobulinemia (X-LA), or Bruton's hypogammaglobulinemia, is characterized by extremely low immunoglobulin levels in most patients. Babies born with this particular form the disease have virtually no peripheral B cells and suffer from recurrent bacterial infections. X-LA is caused by a defect in Bruton's tyrosine kinase (Btk), which is required for signal transduction through the pre-BCR and BCR. There are also immunodeficiencies linked to B cells. One of these diseases is the X-LA. this diseases is liked to a defect in the Btk kinases which is involved in the pre-BCR and BCR signaling cascade. Btk is directly activated by syk which is activated by lyn. So in other words the aggergation of BCR or Pre-BCR on the surface of the cell leads to the activation of Btk and in the absence of Btk the cascade is broken, and there will be no survival of those B cells and therefore a very low number of B cells in this patient. This disease (X-LA) is more server then hyper-IgM syndrom because in this case all of the B cells are gone. in the Hyper-IgM case we have some B cells (that are T cell independent)
What are secondary immunodeficiencies?
In addition to the inherited primary immunodeficiencies, there are also acquired (secondary) immunodeficiencies. Although AIDS resulting from HIV infection is the best known of these (and the most common), other factors, such as immunosuppressive drug treatment, metabolic disease, or malnutrition, can also impact immune function and lead to secondary deficiencies. HIV/AIDS has claimed millions of lives worldwide. Furthermore, it is estimated that as of 2016, 36.7 million people worldwide were living with HIV infection. Although the numbers of new cases have decreased in recent years, they remain doggedly high. secondary immunodeficiencies can arise bc of malnutrition, metabolic disease, or even immunosurrpiessive drug treatment
what is the course of an HIV infection?
Infection with HIV causes gradual and severe impairment of immune function, marked by depletion of CD4+ T cells, and if untreated, usually results in death from opportunistic infections or cancers. HIV-1 infection occurs in three phases: 1. Acute phase •Spike in HIV levels in blood •Eventually brought mostly under control by production of anti-HIV antibody 2. Asymptomatic phase •Lengthy, possibly years •Gradual decrease in CD4+ T cells and increase in viral load 3. AIDS •Crash in CD4+ T-cell numbers •High levels of HIV in blood during the acute phase the HIV virus spikes and antibodies are expressed to keep the virus in check. and thats the point of serocoversion where we have antibodies being expressed that can keep the viral loan fairly low. during the asymptomotic phase the viral load is increasing but the amount of CD4 t cells is decreasing. but why do t cells decrease? well it turns out that while the virus is replicating and increasing its viral particles the exit of those viral particles from the t cells in fact kills the t cells and because of this the amount of t cells available decreases in the aids phase the t cell numbers crash and viral load increases and if left untreated death will result of an infection or a cancer An individual is said to have AIDS when the number of CD4+ T cells in the blood drops below 200/μl; the individual then becomes susceptible to opportunistic diseases.
What is leukocyte adhesion deficiency?
Many immunodeficiencies affecting innate immunity are due to defects affecting myeloid cells, especially impaired functions of phagocytes. These include impaired phagocyte migration, production of reactive oxygen species and reactive nitrogen species, lysosomal function, and macrophage activation by microbes. Affected individuals suffer from increased susceptibility to infections, especially from bacteria. Bear in mind, also, that disruptions to innate immune components may also impact adaptive responses. Leukocyte adhesion deficiency: This disease is caused by an abnormality in the gene for the common β chain of LFA-1, Mac-1, and gp150/95 integrin adhesion molecules: •Limits leukocyte recruitment to inflamed areas •Higher susceptibility to bacterial and fungal infections •Severity of defect varies for unknown reasons so we've seen immunodeciencies that effect T cells and B cells, now lets move towards the myeloid lineage and think of deficiency that can also effect innate immunity. So in this case you can think of leukocyte adhesion deficiency. So for leukocytes (which is a white blood cell such as a neurophile) to reach its specific target in the tissue, it has to role along the surface of the tissue, have permeant arrest, and then extravasion is linked to the high affinity interactions between intergrin proteins expressed on the surface of the leukocytes and ligand found on the surface of the endothelium. Well if the β chains LFA-1, Mac-1, or gp150/95 are absent, then the high affinity interactions between the WBC and the endothelium are not going to occur which will prevent the recruitment of leukocytes to one particular site. furthermore effector T cells which also relie on the same mechanism in order to get into tissues is also going to be nonfunctional. Therefore this leukocyte adhesion deficiency can be seen an a defect in innate immunity but it really it going to effect any WBC that has to traffic from one area to another bc most of these trafficing events depend on intergrin
what is Mendelian susceptibility to mycobacterial diseases?
Mendelian susceptibility to mycobacterial diseases: A set of immunodeficiency disorders has been grouped into a mixed-cell category based on the shared characteristic of single-gene (Mendelian) inheritance of susceptibility to mycobacterial diseases (MSMDs). Defects in genes encoding proteins (marked by a red X) in either the IL-12 activation and signaling pathway (NEMO [downstream of TLR], IL-12, IL-12Rβ chain, and the associated TYK2 signaling molecule) or the IFN-γ pathway (e.g., IFN-γR or the related STAT1 signaling molecule). The production of IFN-γ by TH1 cells, important for clearing intravesicular infections, is activated production of IL-12 by antigen-presenting cells. These deficiencies lead to a general problem in getting rid of intracellular bacterial infections (such as those by mycobacteria). another series disease called Mendelian susceptibility to mycobacterial diseases that is linked to an effect in the innate immune system this is not looking at one particular gene defect and its consequences but rather a group diseases that have one clinical manifestation (susceptibility to mycobacterium) but is linked to several different genes. SO those defected genes might be those that encode for the receptors for IL-12 or IL23 or a defect in the interlukins themself so IL-12 or IL-23 or even a defect in the IFN-γR or a defect in NEMO which is part of the toll like receptor signaling cascade. So what are we talking about here? so a defect in any of these genes prevents a transmission of signal through IL-12 or IL-23 to a TH1 cell which normally would lead to the production of IFN-γ which wold be a normal response to a macrobacterium infection. So if there is no signaling from the macrophage to the TH1 cell that macrobactium infection will be hard to clear furthermore, some people have a defect in their IFN-γ receptor which is basically the same as not secreting IFN-γ in the first place and hence the phagocyte cannot active signaling cascades to activate phagocytosis. these are extracellular defects but there are also intracellular defects such as defects in TYK2 which is fundamental to the signaling cascade downstream of the IL-12/23R would also lead to a susceptibility to mycobacterial diseases. Furthermore a defect in STAT 1 which is a target for JAK1/2 which activates macrophages would lead to susceptibility to mycobacterial diseases (so a defect in STAT 1 would result in the inability to active macrophages) And finally a defect in NEMO would lead to an impaired response to macrobacterium. so these disease all involve a susceptibility to mycobacterial diseases but they each have different clinical manifersations.
what is the main site of HIV replication? what feedback loop occurs here?
Studies have shown that the gut may be the main site of HIV replication and CD4+ T-cell depletion, the latter starting as early as the acute stage of infection. Numbers of CCR5+ CD4+ T cells in the intestine may drop by 60% to 80% within the first 3 weeks after infection. Subsequent investigations of the association between the GI tract and HIV have suggested that intestinal TH17 cells, which express both the CCR5 and CXCR4 coreceptors, are a primary target for infection and destruction. Destruction of these cells and disruption of the integrity of the mucosal barrier in the GI tract allow the passage of microbes and their products across the epithelial layer into the body, explaining some of the rampant immune stimulation and inflammation that is characteristic of HIV infection. In a deadly feedback loop, this immune stimulation generates yet more activated CD4+ cells, the favored targets for HIV infection and replication. whats interesting is that the gut is one of the main HIV replication sites. in individuals who are HIV+ there is a dermatic decrease of t cells in the GI track and to fix this the body trys to secrete more t cells to the GI track allowing for the virus to infect more t cells
what is the causative agent of AIDS?
The causative agent of AIDS is the retrovirus HIV-1. HIV-1 is of the lentivirus genus, which display long incubation periods. Retroviruses carry their genetic information in the form of RNA, and when the virus enters a cell this RNA is reverse-transcribed (RNA to DNA, rather than the other way around) by a virally encoded polymerase enzyme, reverse transcriptase. This complementary cDNA copy of the viral genome is then integrated into the cell's chromosomes, where it is replicated along with the cell's DNA. If the provirus is actively transcribed to form large numbers of new virions (virus particles), the cell lyses. Alternatively, the provirus may remain latent in the cell until some activation signal starts the expression process. There are several subgroups of HIV-1 and HIV-1 group M is responsible for HIV/AIDS pandemic. A close retroviral cousin of HIV-1 called HIV-2 was isolated from some AIDS sufferers in Africa. Unlike HIV-1, its prevalence is limited mostly to areas of western Africa, and disease progresses much more slowly, if at all. Nonhuman primate Simian immunodeficiency virus is believed to be original source of HIV-1 and HIV-2. AIDS is a disease caused by a virus called HIV-1 which is a retrovirus (so it is an RNA virus) and it is catarterized by a very long incubation time. The viral RNA genome is transcriped into a cDNA and then integrated into host genomic DNA to than promote the expression of viral proteins and the formation of new viral particles. SO HIV-1 is the causative agent in AIDS and specifically HIV-1 M is the subgroup responsible for the HIV/AIDS pandemic. There is also a close cousin of HIV-1 called HIV-2 which is found mainly in Africa but this one progresses much more slowly
what is a primary immunodeficiency?
To date, more than 300 different genetic defects have been identified that cause primary (inherited) immunodeficiency. Theoretically, any component important to immune function that is defective can lead to some form of immunodeficiency. Collectively, primary immunodeficiency diseases (PIDs) have helped immunologists to appreciate the importance of specific proteins and cellular processes that are required for proper immune system function. Overall the prevalence of immunodeficiency has been estimated as one per ~500 individuals in the United States. Primary immunodeficiency diseases vary in severity from mild to fatal if the defect is not corrected or if infections are not prevented. Primary immunodeficiency diseases can be loosely categorized as affecting innate or adaptive responses. But remember, either the humoral or the cell-mediated components of the immune system can be affected. immunodeficiencies can effect the innate and adaptive immune system and the humoral or cellular components
what are some of the HIV treatment possibilities?
Treatment of HIV infection with antiretroviral drugs that target specific steps in the viral life cycle, especially in combination, can lower the viral load, provide relief from some symptoms of infection, and prevent infection of others. These targets are: •Chemokine receptor antagonists - to prevent attachment •Fusion inhibition •Reverse transcriptase inhibition •Integrase inhibition •Protease inhibitors the main targets in tritheropy Antiretroviral therapy of pregnant women and newborns has greatly reduced mother-to-child transmission of HIV worldwide. Antiretroviral drugs can also be taken prophylactically to prevent infection of at risk population. A vaccine may be only way to stop HIV/AIDS epidemic, but unfortunately years of effort have not been fruitful in identifying a vaccine that can protect the human population.