Chronic inflammation Flashcards
What is chronic inflammation?
- Chronic inflammation is an adaptive response triggered by noxious stimuli such as such as infection and tissue injury; just like acute inflammation it facilitates the localisation of circulation cells and molecules involved in defence to the stimulus site.
- The dysregulation of acute inflammation leads to persistence and thus treating these conditions requires an understanding of the pathogenesis.
- Arguably an even better solution is to prevent its onset through an understanding of the bridge between acute and chronic inflammation.
What are the histological signs that differentiate chronic inflammation from acute inflammation?
- Hard (indurated), red (erythematous) swelling
- Mononuclear cell infiltrate (macrophages, lymphocytes and plasma cells)
- Little oedema
- Angiogenesis
- Collagen deposition
Introduciton to rheumatoid arthritis
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disease that primarily affects the joints, leading to synovial hyperplasia and bone destruction. It has an approximate occurrence of 4 in 10,000 people and greatly reduces the quality of life of suffers alongside increasing their risk of coronary heart disease.
Introduction to tuberculosis
Tuberculosis (TB) is one of the ancient and deadliest disease of mankind, still posing a major health, social and economic burden at a global level. The WHO estimates 1.8 billion people (1/4 of the world population) are infected with TB, with only 5-10% developing symptoms. The lack of an effective vaccine & the long and expensive drug regimens means mTB infections can be persistent, chronic and lead to death.
Compare the effects of smoking, air pollution and gender on the risk factors for RA and TB
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Smoking
- Smoking increases the risk factor for both diseases but through different mechanisms.
- It is hypothesised that smoking causes epigenetic changes which results in hypomethylation of certain DNA elements contributing to RA
- Smoking also reduces cilia function thereby disrupting the ciliatory escalator increasing chance of getting infected.
- Smoking increases the risk factor for both diseases but through different mechanisms.
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Dust inhalation & air pollution
- For both conditions, dust inhalation and air pollution similarly increases risk of developing both conditions.
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Gender
- Interestingly, women are 2/3 more likely to develop rheumatoid arthritis than men
- This is thought to be due to the stimulatory effects of oestrogen on the immune system but the exact role remains controversial and more research is needed
- However, tuberculosis is more common in men.
- There are many hypotheses such as:
- Women having difficulty accessing TB servicesTB
- More difficult to diagnose in women
- TB lung lesions might not be in severe in women.
- There are many hypotheses such as:
- Interestingly, women are 2/3 more likely to develop rheumatoid arthritis than men
Compare the genetic components of RA and TB
Rheumatoid arthritis has a strong genetic component as evidenced by twin studies and genome wide association studies (GWAS). Twin studies have estimated that heritability of RA is around 60% furthermore, the HLA gene which encodes MHC molecules with a shared epitope show a strong association with RA. The specific amino acid motif encoded by some alleles of the HLA-DR locus are significantly associated with an increase risk by binding citrullinated peptides. Citrullination is the conversion of the amino acid arginine in proteins (commonly histones, collagen and fibronectin) into the amino acid citrulline. Stressors such as cigarette smoke can act on mucosal cell sites and active peptidyl arginine deaminase and thus there is an interplay of genetic and environmental factors.
In contrast, mutations in the genes encoding molecules involved in the immune response to TB such as IL-12, IFN-g, andSTAT1(a signal transducer in the IFN-g cascade) confer an increasedsusceptibility to severe TB.
Describe the initiation step for RA
Antigen-Loading – Rheumatoid arthritis
In most patients, the pathogenesis of RA begins before the clinical disease is evident. Following neo-epitope generation (e.g. citrullination), the altered peptides bind to and are presented on MHC I proteins on mucosal cells especially those containing a shared epitope. These are recognised as non-self by the pattern recognition receptors (PRRs) on antigen presenting cells such as dendritic cells. These cells migrate to the secondary lymphoid organs (SLO) carrying peptides taken up from the extracellular matrix and apoptosed cells. These are presented to T-cells by dendritic cells resulting in B-cell activation.
Describe the initiation step for TB
Cell entry, replication & immune evasion – Tuberculosis
Unlike rheumatoid arthritis, tuberculosis is transferable and by being very slow and having few symptoms, there is a high contact and transmissibility rate. Tuberculosis is transmissible in 2 phases of the course of the disease: primary disease and post primary disease. Primary disease is the failure to resolve the primary infections which results in progression in 5% of cases. 90% of people enter a latent infection phase, where the mTB remains controlled by the immune system. In approximately 5% of cases, there Is reactivation of latent mTB resulting in post-primary disease and this incubation period can range from 3 months to 33 years.
Whereas rheumatoid arthritis initiation is predominantly through the adaptive immune system, Tb is initiated through the innate immune system. Transmission of TB is through the inhalation of aerosol droplets from the respiratory tract of infected cells. These may be released by coughing or sneezing and can form droplet nuclei that can be inhaled into the lower respiratory tract and result in primary infection. M. tuberculosis is then taken up by alveolar macrophages via receptor-mediated endocytosis via the binding of bacterial surface ligands such as mannose and C3b to membrane receptors of the macrophage such as mannose receptor and CR3 respectively. This receptor activation stimulates the uptake of the bacterium into an endocytic vesicle known as the phagosome.
Once in the phagosome, mTB persists by a number of mechanisms that aid immune evasion including: resistance to antimicrobial stress, arresting phagosome maturation, preventing lysosome fusion and altering metabolism. The mTB resists the anti-microbial stress of macrophages by detoxifying the reactive oxygen species (ROS) by the production of superoxide dismutase and catalase (converting H2O2 into H2O + O2). The acidification is prevented by the secretion of NH4+,which inhibits the phagosomalproton pump.
mTB replicates within the phagosome or cytosol generating a large number of bacteria. Iron is essential for the mTB replication; it is sequestered from the intracellular fluid by a number of mechanisms including exochelin and MRAMP.
Describe the targeting stage of RA
The dendritic cells bind T-cells with complementary T-cell receptors to the presented antigens in the stroma of secondary lymphoid organs. The activated T-cells then undergo clonal expansion and migration to the B-cell areas where they bind to B-cells with the antigen they have been primed for. B-cells undergo activation and clonal expansion, producing antibodies that are reactive to these modified self-proteins. Antibodies include: rheumatoid factor (targeting the Fc portion of IgG) and anti-citrullinated protein antibody (against citrullinated proteins). As such, the presence anti-CCP antibodies is used as a diagnostic tool for RA. However, the double hit theory proposes that the presence of antibodies is not sufficient to develop synovitis. An additional hit such as immune complex formation or microvascular disruption is likely to be required to initiate the infiltration of inflammatory cells into the synovium.
The synovium serves two roles: producing synovial fluid (lubricant) and providing nutrients to the cartilage which lacks its own blood supply. It has two layers: the intimal lining (composed of macrophage-like synoviocytes and fibroblast-like synoviocytes) as well as a sub-lining (composed of adipocytes, blood vessels and scattered immune cells). There are 2 key pathogenic changes in the synovium: the expansion of the intimal lining and the infiltration of adaptive immune cells. The proliferation and activation of macrophage-like synoviocytes and fibroblast-like synoviocytes as well as antibody production contribute to the expansion of the intimal lining. The expansion of the intimal lining is also facilitates by the secretion of IL-6, prostaglandins and leukotrienes by fibroblast-like synoviocytes and thus non-steroidal anti-inflammatories (NSAIDs) can be used.
Describe the targeting stage of RA
Host T response – Tuberculosis
M tuberculosis then activates the host immune response which is an important component of pathogenesis. Host tissue damage is mediated by the immune effector mechanisms that M. tuberculosis induces. Pathogen-associated molecular patterns (PAMPs) of M tuberculosis are recognised by pattern recognition receptors (PRRs) of the innate immune system. A number of lipoproteins on the mTB surface ligate TLR2 such as phosphatidyl inositol mannoside (PIM) leading to the activation of the macrophage and secretion of cytokines. These act as chemoattractants for other immune cells including dendritic cells and monocytes.
Similarly to RA, dendritic cell play an important role in pathogenesis with mTB antigens taken up to the lungs to T-cells in the secondary lymphoid organs on MHC I and II. The T-cells activate and undergo clonal expansion followed by differentiation. Firstly, presence of predominantly IFN-gamma from natural killer cells cells and IL-12 stimulates differentiation into TH1 cells. TH1 cells co-ordinating the elimination of intracellular pathogens by secreting IFN-gamma and IL-12 in a positive feedback mechanism; this increases the antimicrobial power of the macrophage (by increasing ROS, reactive nitrogen species as well as inducible nitric oxide synthase producing NO which reacts with other species to form reactive nitrogen species).
Describe the final stage of RA
The invasion of synovial cells into the articular hyaline cartilage is the cardinal sign of rheumatoid arthritis. Macrophages, neutrophils and mast cells contribute to damage by the release of cytokines, collagenases. Fibroblast-like synoviocytes also play a key role as shown by an experiment by Muller-Ladner et al in 1996 in which he took FLS isolates from RA patients and implanted the cells into the synovium of immunodeficient mice. He showed that they invade aggressively into the cartilage by matrix degradation. When this was repeated with FLS from osteoarthritic patients, this was not seen.
The invasive synoviocytes form a tissue at the interface between the cartilage and the bone that becomes vascularised via angiogenesis under the influence of vascular endothelial growth factor (VEGF). This is known as pannus and is a cardinal sign of RA. The bone erosion seen in RA is largely due to the maturation and activation of osteoclasts by: receptor activation of RANK by RANK ligand by T-cells and the secretion of TNF, IL6 and IL-1 by macrophages and FLS. This results in classic symptoms such as: morning stiffness, tenderness, pain during movement and swollen joints.
Describe the final stage of TB
Following primary infection with TB, a Ghon focus is formed. A Ghon focus is a type of granuloma within which the mTB infection is contained; it seen on X-rays as a calcification usually in the mid-zone of the lung. If there is spread to the regional lymph nodes, a primary complex is formed. The Ghon focus/primary complex usually heals in most cases and the infection is controlled by the cell-mediated immunity resulting in latency where there is the control of the infection and no increase on the bacterial load.
Failure of the immune system to control the primary infection results in primary disease for example by the Gohn focus rupturing the pleura leading to a pleural effusion, massive lymphohematogenous dissemination and military TB (severe form of TB which is almost always fatal if untreated).
In most people, the immune response is able to contain the infection within the granuloma. It remains latent in the granuloma, a characteristic sign of TB. A granuloma is defined as an aggregation of macrophages (and often T-cells) that function to contain the pathogen. These granuloma cells may differentiate into epithelioid cells or giant cells (large multinucleate cells formed by the fusion of many infected macrophages). Macrophages around the granuloma may appear “foamy” due to the lipid bodies produced by bacteria preventing the macrophages from pumping out LDL. These granulomas heal by fibrosis and calcification. However, if the primary infection cannot be controlled in the lung or a latently infected person becomes immunosuppressed due to HIV infection, malnutrition or age, the granuloma centre can liquefy by an unknown process and facilitates rapid bacterial replication.
Describe how RA is treated
There are two main types of disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis: synthetic and biological. Methotrexate, a synthetic DMARD acts by inhibition purine metabolism leading to adenosine accumulation, suppression of T-cell activation and inhibition of T-cell adhesion molecule expression. An example of a biologically DMARD includes infliximab (an antibody against TNF), it binds to soluble transmembrane TNF and downregulate TNF induced immune responses including: adhesion molecule expression, cytokine production, matrix metalloproteinase and neutrophil activation. Although these come with risks of increased infection, they are extremely effective in reducing the inflammatory component of the disease.
Describe how TB is treated
The mainstay treatment of tuberculosis is with antibiotics. There are 4 antibiotics used in TB therapy to prevent the emergence of resistance: isoniazid (prodrug that blocks fatty acid synthase and thus mycolic acid synthesis), rifampicin (blocks DNA-dependent RNA polymerase thereby preventing RNA synthesis), pyrazinamide (blocking fatty acid synthase) and ethambutol (inhibiting arabisonyl transferase preventing the formation of the bacterial cell wall). The duration of these treatments is long, around 6 to 9 months. The long therapy is required because mTB is an intracellular pathogen (so protected from drug by macrophage plasma membrane), caseous necrotic material blocks drug penetration, the slow growth of mTB and that there may be metabolically inactive bacteria within the lesion (drugs are only effective on active organisms). Direct observed therapy is an attempt to improve adherence by active monitoring and recording of the consumption of each and every drug dose by an “observer” in order to increase adherence to the medication preventing the mergence of resistance and the patient stopping treatment as their symptoms subside. There has been an increased emergence of multiple drug resistant tuberculosis resulting in the reduced efficacy of mainstay drugs; this has contributed to preventing its control and elimination.
