Mechanisms Of Disease 3: Chronic Inflammation

Front 1

List the cytokines involved in:
1. Vasodilation
2. Vascular permeability
3. Chemotaxis
4. Fever
5. Pain
6. Tissue damage

Back 1

Front 2

What is chronic inflammation?

Back 2

- Long standing inflammation.
- Characterised by cells involved = the chronic inflammatory / mononuclear cells
- Results in tissue destruction, fibrosis and repair → scar tissue and always some loss or function.
- Granulomatous inflammation is one specific pattern of chronic inflammation

Front 3

How does chronic inflammation arise?

Back 3

- May take over from acute inflammation → If disease lasts more than a few days, insult cannot be removed or damage is significant
- May arise de novo
→ Chronic infections, auto-immune disease
→ Chronic irritation
- May develop alongside acute inflammation → In more severe persistent irritation

Front 4

Give 4 specific causes of chronic inflammation

Back 4

1. Persistent infections e.g. syphilis, TB, viral hepatitis, HP related gastritis.
2. Prolonged exposure to toxins, e.g.silica, atherosclerosis endogenous lipids
3. Autoimmune diseases e.g. Graves disease, ulcerative colitis, primary biliary cirrhosis.
4. Non resolving acute inflammation, e.g. bed sores

Front 5

What are the 3 patterns of chronic inflammation

Back 5

1. Lymphocytic → infiltration of lymphocytes e.g. auto-immune thyroid disease, chronic hepatitis
2. Granulomatous → formation of granulomas e.g. TB, sarcoidosis, Crohn's disease
3. Mixed acute and chronic inflammation e.g. chronic active gastritis, ulcerative colitis

Front 6

What cells are involved in chronic inflammation?

Back 6

- Mononucleated cells
1. Macrophages = nucleus cigar-shaped, vesicular chromatin, very pale cytoplasma
2. Lymphocytes = dark round nucleus, very little cytoplasm
3. Plasma cells = clock-faced nucleus
4. Eosinophils

Front 7

Describe the features of the innate and adaptive immune systems

Back 7

Innate:
- No previous exposure required
- Reacts to bacterial wall and virus proteins
- TOL Like receptors (TLRs) = conserved receptors on responsive cells which recognise foreign particles
- Phagocytosis by neutrophils and macrophages carrying TLRs
- Complement activated = cascade of proteins which disrupt membrane

Adaptive
- Previous exposure required
- Response specific to that organism
- Depends on APC processing antigens
- Recruitment of unique lymphoid cells

Front 8

What is Nuclear factor Kappa B (NF-κB)?

Back 8

- Rapid acting primary transcription factor
- Found in the signalling pathway of TLRs on neutrophils and macrophages
- Five members of the NF-κB family
- Present in the cytoplasm and activated by both non-canonical and canonical pathways
- Activated NFκB translocates from cytoplasm to nucleus
- Transactivation of up to 200 genes in inflammatory response, cell proliferation, and cell survival pathways
- Rapid acting = doesn't require transcription itself

Front 9

Describe the features and functions of the macrophage

Back 9

- Derived from blood monocytes
- Different levels of activation
- Phagocytosis and destruction of bacteria and debris.
- Control of other inflammatory cells by means of cytokines.
- Secrete a number of factors involved in tissue destruction and tissue repair.
- Processing and presenting antigen to the immune system.

Front 10

What are the various types of macrophage?

Back 10

Reticuloendothelial system = tissue bound macrophages

Front 11

What are the factors that activate macrophages, and what happens to the macrophage on activation?

Back 11

Macrophage activating factors:
- Cytokines – IFNγ (γ-interferon) from T Cells
- Bacterial endotoxins
- Chemical mediators of inflammation
- ECM proteins

Activation means
- Epithelioid cell type (known as this when they have developed voluminous cytoplasm)
- Increased size = increased cytoplasm
- Increased metabolic rate = subcellular apparatus for protein synthesis develops
- Increased phagoctyic activity
- Often form multinucleated giant cells by fusion of active macrophages

Front 12

Describe the secretions of the activated macrophages

Back 12

1. Tissue damaging agents
- Proteases, Collagenase, and Lipases → dissolution of extracellular material
- Neutrophil chemotactic factors
- Coagulation factors
- Arachidonic acid derivatives = mediators of acute inflammation
- Nitric oxide and highly reactive oxygen metabolites → bacterial and cell killing

2. Pro-fibrotic tissue repair factors
- Growth factors (PDGF, FGF, TGFb) = stimulate growth of blood vessels, and division and migration of fibroblasts
- Fibrogenic cytokines, IL-1, TNFα = stimulate fibroblast proliferation and collagen synthesis, which are important in the reparative response
- Angiogenic factors
- Remodelling collagenases

All factors are secreted in varying amounts depending on the type of stimulation on the cell

Front 13

Describe the process of accumulation of macrophages

Back 13

1. Recruitment from circulation via endothelial receptors and chemotaxis - C5a, IL8 Chemokines (MCP-1), TGF Beta.
2. Immobilization - Macrophage inhibitory factor, oxidised lipids.
3. Proliferation.

Front 14

What are lymphocytes?

Back 14

- Normally present in lymph nodes and other tissues
- T cells release cytokines and have cytotoxic functions = Thymus selects the useful, neglects the useless and destroys the harmful.
- B cells responsible for antibody production = Bone marrow
- Both types undergo maturation in secondary lymphoid tissue (lymph node spleen and mucosal associated lymphoid tissue)

Front 15

Describe the features of B lymphocytes and Plasma cells

Back 15

- B cells found in the cortex of lymph nodes (follicles)
- Naïve Bcells are non antigen sensitized
- Mature in the primary follicle following APC antigen presentation, with T helper cell
- Undergo IG gene rearrangement with selection of successful clone
- Matures to memory B cell or plasma cell
- Plasma cells are immunoglobulin factories
- Clonal i.e. produce one unique antibody per cell

Front 16

Describe the features of T cells

Back 16

- TCR is unique to one antigen
- T4 Helper/Inducer need Ag+MHCII
• TH1 release IFNγ & IL2. Found in cellular response and granulomatous disease as well as Immunoglobulins
• TH2 release IL4 IL5 & IL13 → Facilitates Ab production
- T8 Supressor/cytotoxic need Ag+MHC1

Front 17

Describe the features of eosinophils and mast cells in the chronic immune response

Back 17

Eosinophils
- Have membrane bound IgE, and important in IgE mediated reactions and parasites infections (allergy etc).
- Eotaxin is important in recruitment.
- Release Major Basic Protein, a cationic protein toxic to many parasites.
- Present in some tumours.
Mast cells
- Tissue bound = also have membrane bound IgE
- Important in anaphylaxis reaction
- Important in acute and chronic inflammation
- Release cytokines

Front 18

Describe 4 possible complications of chronic inflammation

Back 18

- Never get complete resolution back to normal
1. Fibrosis - TB, 'hour glass' stomach = distorts organs → strictures etc
2. Scarring with dysfunction e.g. cirrhosis (chronic hepatitis), intestinal stenosis (Crohn's)
3. Atrophy e.g. gastric mucosa in chronic auto immune → left with simple tubular crypts, thin mucosa and high surface mucous cells
4. Metaplasia e.g. bronchus, oesophagus, and bladder (transitional to squamous)

Front 19

Describe the regulation of inflammation

Back 19

- Elimination of noxious agent leading to reduction of pro-inflammatory mediators -PGs, Leukotrienes, TNF etc.
- Regulatory T cells under control of FoxP3 → TH2, TR1
- Repressing cytokines IL10, TGFβ and receptor fragments for TNF, Annexin A-I (activates leukocytes and sends them to the site of infection directly, inhibiting neutrophil extravasation and down regulates the magnitude of the inflammatory response)
- Systemic hormones
• Adrenal glucocorticoids, adrenaline and α-melanocyte stimulating hormone (αMSH)
• Autonomic nervous system - vagal suppression via nicotinic receptors on macrophages

Front 20

Describe the features of granulomatous inflammation

Back 20

- Chronic inflammation characterised by the presence of granulomas.
- Granulomas are collections of macrophages, often with giant cells.
- Granuloma formation
• Response to chronic (persistent) low grade antigen stimulation.
• Delayed hypersensitivity reaction.
• Foreign material
• Insoluble antigens
- TH1 cells - secrete
- IL2 IFNγ = promote macrophage accumulation

Front 21

What are the 3 types of granulomata?

Back 21

1. Necrotizing e.g. TB and Wegner's granulomatosis
2. Naked e.g. Sarcoidosis (no necrosis)
3. Foreign body

Front 22

List 7 granulomatous diseases

Back 22

Infections
1. Mycobacteria e.g. TB
2. Syphilis
3. Cat scratch disease
Autoimmune
4. Rheumatoid nodules
Idiopathic
5. Crohns disease
6. Sarcoidosis
Foreign body (7)

Front 23

Describe the features of giant cells

Back 23

- Several macrophages fuse to form giant cells = nuclei exist in the cytoplasm and many cells contribute to the cell membrane
- Often (but not always) in granulomatous inflammation
- Major role in phagocytosis of foreign bodies
- Langhans is a characteristic giant cell seen in TB
- Distinguished by the arrangement of the nuclei = horse-shoe shaped

Front 24

Describe the features of tuberculosis

Back 24

- Archetypal chronic inflammatory disease

◘ Causes:
- Mycobacterium tuberculosis hominis or Mycobacterium tuberculosis bovis (rare)
- Various other mycobacterial species can cause infection in the immunocompromised.
- Aerobic bacteria with a waxy coat
- Requires special stain (Ziehl Neelson) acid alcohol fast (AFB)

◘ Epidemiology:
- 8 million people affected worldwide
- 2 million die from TB
- Particularly prevalent in Sub-Saharan Africa, India, and South East Asia.
- Multi-drug resistant strains becoming common especially in Russia.
- Associated with poor socioeconomic conditions.
- Less common in Britain largely due to public health measures, and vaccination.
- TB is a notifiable disease

◘ Primary TB:
- Initial infection small granuloma = Gohn focus → casseous necrosis surrounded by fibrous tissue
- Involvement of hilar lymph node = Gohn complex
- Usually heals with minor scarring
- Occasionally progressive primary TB (TB proper)
• Massive hilar lymphadenopathy
• TB pneumonia
• Miliary TB

◘ Latent Period:
- Individuals well and disease free.
- Small granulomata in lungs, often fibrosed, and barely visible.
- Low mTb load often not detectable, sputum negative.
- Patients not infective.

◘ Secondary TB:
- Apex lungs (aerobic bacteria and need high O2 tension).
- Re-activation of primary infection
- Variable and unpredictable disease.
- Particularly likely to breakout in “run down” patients.
- Granulomas with caseation = central necrosis.
- TH1 control via cytokines chiefly IFNγ.

◘ Outcomes of Secondary TB
= Arrest fibrosis scaring
- Cavitation of large granulomas = Tubercle
• Erosion into bronchus - infectious patients
• Erosion into pulmonary vessels - Consumption
• Pleura - tuberculous empyema
- Erosion in pulmonary artery or vein - Miliary TB
• Distant blood borne spread
• Lymph nodes kidneys, adrenal gland (Addison’s disease), fallopian tubes (infertility), epididymis, brain, skin (lupus vulgaris)

Front 25

Describe the features of sarcoidosis

Back 25

- Idiopathic
- Systemic disease with many manifestations
- Pulmonary nodules with lymphadenopathy common
- Most commonly affects women, especially Afro-Caribbean and Caucasians
- Unknown in Asian and Chinese
- Small well formed non-caseating granulomas (mortar-wall granulomas) with histiocytic giant cells
- Frequently accompanied by fibrosis
- Affected patients most commonly present with clinical disease related to lung involvement, or with evidence of bilateral hilar lymph node enlargement
- Diagnosis of exclusion: fungi, mycobacterium berylliosis etc.
- Treatment: corticosteroids e.g. prednisone, tapered over a 6-month period, or (where steroid-resistance, or side-effects) methotrexate. For patients with advanced sarcoid-induced pulmonary fibrosis, lung transplantation is the only hope for long-term survival

Front 26

Describe the features of Crohn's disease

Back 26

- Gastrointestinal granulomatous disease with systemic manifestations.
- Idiopathic, but polymorphisms in NOD 2 (a co-factor in the NaK3 pathway) have recently been implicated.
- Affects any portion of GIT most commonly terminal ileum.
- Caucasians and western populations most commonly affected
- Transmural chronic inflammation with small granulomata and fissure ulcers → cobblestone appearance
- Granulomas not in all cases, and are small where present

Front 27

Describe the features of leprosy

Back 27

- Chronic granulomatous disease involving Mycobacterium leprae
- Infection results in a clinical disease in a minority of patients
- Affects skin and peripheral nerves
- Can lead to irrepairable nerve damage and disability
- 3 types:
1. Lepromatous = multi-bacterial form with strong humoural response but little cell-mediated immunity → wide-spread lesions, disfiguring nodularity of the skin. Lesions contain lymphocytes, plasma cells and macrophages filled with organisms
2. Borderline
3. Tuberculoid = pauci (low)-bacterial form with few skin lesions. Focal areas of skin pallor and anaethesia due to early involvement of nerves. Basic lesion is a follicular granuloma (tubercle) similar to a true tubercle follicle. Cell-mediated immunity is well-developed
- Treatment = Dapsone (blocks folic acid synthesis → bacteriostatic) and Rifampin (Inhibits DNA-dependent RNA polymerase → bactericidal) once a month, plus clofazimine (slowly bactericidal, inhibits growth, anti-inflammatory) once a month for a year. Educate patients on nerve damage and properly treat any effects of nerve damage to prevent deformity. Surgical drainage of nerve abscesses can restore function if noted quickly
- Significant associations in SNPs in five genes including NOD2, HLA-DR, RIPK2
- Associations stronger in multi-baciliary form compared to the pauci-baciliary form

Front 28

Describe the features of syphilis

Back 28

- Sexually transmitted granulomatous infection caused by T. pallidum
- Primary syphilis = during the first 3 weeks of infection.
• Formation of hard chancre characterised by lymphocytes and plasma cells (not polymorphs = not an abscess and healing occurs without scarring)
- Secondary syphilis lesions are quite variable in their manifestations.
• Widespread mucocutaneous lesions are observed over the entire body. Most often, the lesions are macular, discrete, reddish brown, and 5 mm or smaller in diameter
• All such lesions contain treponemes. Of these, wet mucous patches are the most contagious.
• Histologically, the inflammatory reaction is similar to but less intense than that of the primary chancre.
- Tertiary syphilis
• The pathognomonic lesion of tertiary syphilis is the gumma, a granuloma which is characterized by a center of necrotic tissue with a rubbery texture (coagulative necrosis.
• Gummas principally form in the liver, bones, and testes.
• Histological examination shows palisaded macrophages and fibroblasts, as well as plasma cells surrounding the margins.
• Treponemes are rarely visualized or recovered from these lesions.
- Treat with antibiotics e.g. penicillin