The Inflammatory Response pdf - نظري

Unit 3 - Immunological factors in disease

Lecture 3 - The Inflammatory
Response

Inflammation is the response of tissues to injury or
infection and is necessary for normal repair and healing

Physiology & pathology of inflammation

Acute inflammation



It is the result of rapid and complex interplay between the

cells and soluble molecules of the innate immune system.



When there is an infection or inflammation in the tissue,

leads to infiltration of phagocytic cells (N, Macro) & release:

1) Enzymes (Cyclo-oxygenase & nitric oxide synthase). It

leads to release (prostaglandins, histamine, kinins,
anaphylotoxins & nitric oxide)

2) Cytotoxines (IL1, TNF, IL6)

This leads to:
Vasodilation, increased vascular permeability, increased
production of N in the bone marrow, release of insulin
from pancreas, release glucocorticoids & catecholamines
from adrenal, increase heart rate, increase synthesis of
acute phasr protein and amyloid A by the liver, low blood
pressure, fever, enlarged lymph nodes and fibrinogen
plays important role in wound healing.

Control mechanisms of inflammation

Acute phase proteins



α1-antitrypsin and α1-antichymotrypsin control the pro-
inflammatory cascades.



Antioxidants such as haptoglobin and manganese

superoxide dismutase scavenge for oxygen free radicals.



Increased iron-binding proteins such as transferrin, ferritin &

lactoferrin decrease the iron available for uptake by bacteria.

Resolution of inflammation

This involves active down-modulation of inflammatory
stimuli and repair of bystander damage to local tissues.

1) Extravasated neutrophils undergo apoptosis and are

phagocytosed by macrophages, along with the remains of
microorganisms.

2) Macrophages also synthesise collagenase and elastase,
3) Macrophage-derived cytokines, including transforming

growth factor (TGF)-β and platelet-derived growth factor,
attract fibroblasts and promote the synthesis of new collagen

4) Angiogenic factors stimulate new vessel formation.

Sepsis and septic shock



Septic shock is the clinical manifestation of overwhelming

inflammation. Failure of normal inhibitory mechanisms

results in excessive production of pro-inflammatory
cytokines by macrophages, causing hypotension,
hypovolaemia, decreased perfusion & tissue oedema.



Damage to the vascular endothelium and further

increasing capillary permeability.



Direct activation of the coagulation pathway ends with

clot formation.



The clinical manifestations:

1)  Cardiovascular collapse
2)  Acute respiratory distress syndrome
3)  Disseminated intravascular coagulation
4)  Multi-organ failure and often
5)  Death



Cause: infection with Gram-negative bacteria, because

lipopolysaccharide is particularly effective at activating
the inflammatory cascade.

Chronic inflammation



Failure to remove an inflammatory stimulus.



Persisting microorganisms stimulate the ongoing

accumulation of neutrophils, macrophages and activated T
lymphocytes & deposition of fibrous connective tissue
ending with granuloma.



Eg, (TB, Leprosy) because this MO is protected with

thick cell wall,

Investigations in inflammation

1)  Complete blood picture: Leukocytosis
2)  Platelets count: may be increased
3)  Erythrocyte sedimentation rate (ESR)
4)  Blood film: normocytic normochromic anemia
5)  C-reactive protein & complement: increased
6)  Albumin: reduced
7)  Plasma viscosity

C-reactive protein



Is an acute phase protein synthesis in the liver.



It is opsonizes invading pathogens.



It’s level increased within 6 hours of an inflammatory
stimulus.



It indicates acute inflammation



Its half-life = 19 hours



It is used to monitor disease activity.

Erythrocyte sedimentation rate (ESR)



It is an indirect measure of acute phase protein.



It measures the rate of fall of RBC through plasma &

aggregation of erythrocytes

Unit 3 - Immunological factors in disease



Normally RBC do not aggregate with each other because

of their repellent negative charge.



Plasma protein is positive charge & act to neutralize the

surface charge of RBC.



When there is an increase in plasma protein particularly

fibrinogen, overcome the repulsive forces causing stack of
RBC (rouleaux)



It is measuring plasma protein composition, concentration

& RBC morphology.



It is increased (1) in acute inflammation, when there is an

increase in acute phase protein. (2) when there is an
increase in IgG, IgM & IgA.



It is deceased when there is an abnormality in RBC

morphology like spherocytosis, sickle cell anemia.

Plasma viscosity

It measures plasma protein concentration
It is affected by concentration of large plasma proteins
(fibrinogen, Ig [IgM])

Presenting problems in inflammation

Unexplained raised ESR

The ESR should not be used as a screening test for the
presence of disease in asymptomatic patient.

Clinical assessment

There is an extreme elevation of ESR ˃ 100 mm/hr in the
absence of significant disease.

Investigations



CRP, Serum Ig, Urine electrophoresis



Full blood count; anemia, leukocytosis, neutrophilia,

abnormal lymphocytes



Liver function test



Blood & Urine cultures



Imaging: Chest X-ray, Abdominal CT scan, Abdominal &

pelvic ultrasound, MRI, Echocardiography and Isotope scan

Periodic fever syndromes

These rare disorders are characterized by recurrent
episodes of fever and organ inflammation associated with
an elevated acute phase response.

Familial Mediterranean fever



This is the most common of the familial periodic fevers,

predominantly affecting Mediterranean people, including



Arabs, Turks, Sephardic Jews and Armenians.



It results from mutations in pyrin gene.



Characterized by painful attacks of fever associated with

peritonitis, pleuritis and arthritis, and lasts from a few
hours to 4 days.



CRP is elevated.



Colchicine is the treatment of choice.

Hyper IgD syndrome



It is characterized attacks of fever, abdominal pain,

diarrhoea, lymphadenopathy, arthralgia, skin lesions and
aphthous ulceration.



Laboratory features include an acute phase response

(elevated CRP & ESR) and markedly elevated IgD



It has mainly been described in the Netherlands & France.



It is AR disease.



All patients with syndrome have mutations in the gene for

mevalonate kinase which is involved in cholesterol
metabolism.



No specific treatment is available.

TNF receptor associated periodic syndrome



Also known as TRAPS or familial Hibernian fever.



Is a periodic fever syndrome associated with mutations in

a receptor for the molecule tumor necrosis factor (TNF)
that is inheritable in an autosomal dominant manner.



Individuals have episodic syndromes such as recurrent

high fevers, rash, abdominal pain, joint/muscle aches &
puffy eyes.



It causes recurrent episodes of fever that typically last 1-3

weeks that are associated with chills & severe muscle pain
in the trunk & the arms.



Patients develop a red & painful rash from the trunk to the

arms & legs, abdominal pain with nausea, vomiting &
diarrhea are common, as are red, swollen eyes. Other
important features include chest pain due to inflammation
of the membrane surrounding the lungs or heart.



Laboratory findings

1)  Neutrophilia
2)  Increased CRP
3)  Elevated ESR
4)  Low level of serum soluble type 1 TNF receptor
5)  Molecule analysis of TNFRSF1A gene
6)  Screening for proteinuria



Several medications have been studied for the treatment

of TRAPS including: Corticosteroids, Infliximab, Soluble
TNF receptor therapy.

Unit 3 - Immunological factors in disease

Amyloidosis



It is a disorder resulting from abnormal & insoluble

protein (amyloid) deposits extracellular in body tissues.



It consists of fibrils of specific protein linked to glucose-

aminoglycans, proteoglycans & serum amyloid protein.



It is either hereditary or acquired.



It is either localized or systemic.

Hereditary systemic amyloidosis



It is systemic amyloidosis.



Production of abnormal protein with abnormal structure.



It is AD due to mutation in transthyretin retinol



Transthyretin (TTR) is a serum & cerebrospinal fluid

carrier of the thyroid hormone thyroxin (T4) and retinol –
binding protein bound to retinol. This is how transthyretin
gained its name, transports thyroxine & retinol. The liver
secretes transthyretin into the blood & the coroid plexus
secretes TTR into the cerebrospinal fluid.



Characterized by neuropathy, cardiomegaly & renal

involvement

Acquires systemic amyloidosis

1) Reactive amyloidosis

 This is the result of another chronic inflammatory disease

such as lupus, rheumatoid arthritis, tuberculosis,
inflammatory bowel disease (Crohn’s disease & ulcerative
colitis) & certain cancers.

 It most commonly affects the spleen, kidneys, liver,

adrenal gland & lymph nodes.

 AA means the amyloid type A protein causes this type of

amyloidosis.

 90% of the patients developed non-selective proteinuria or

nephrotic syndrome.

2) Light chain amyloidosis

 AL occurs when a specialized cell in the bone marrow

(plasma cell) spontaneously overproduces a particular

protein portion of an antibody called the light chain. (This
is why it is coded as AL)

 Can occur with a bone marrow cancer of plasma cells

called multiple myeloma, Monoclonal gammmaopathy.

 Requiring chemotherapy treatment.
 It is characterized by neuropathy, cardiomyopathy,

proteinuria, amyloid nodules.

3) Dialysis associated amyloidosis

 Hemodialysis-associated amyloidosis is a form of

amyloidosis associated with chronic renal failure.

 Long-term hemodialysis results in a gradual accumulation

of β

microglobulin, a serum protein in the blood. It

accumulates because it is unable to cross the dialysis filter

 Β

micrglobulin is a major constituent of amyloid fibrils.

It has been shown that through accumulation, it invades
synovial membranes & osteoarticular sites. As a result, it
causes destructive osteoarthropathies such as

4) Senile systemic amyloidosis

  Age ˃ 70 years
  Normal transthyretin protein deposited in tissues.
  Usually asymptomatic.
  Affect ˃ 90% of 90 years old persons.

Diagnosis



A tissue sample of abdominal wall fat, the rectum or a

salivary gland can be examined in biopsy for evidence of
characteristic amyloid deposits.



The tissue is treated with various stains. The most useful

stain in the diagnosis of amyloid is Congo red, which,
combined with polarized light makes the amyloid proteins
appear apple-green on microscopy.



The nature of the amyloid protein can be determined by

various ways: the detection of abnormal proteins in the
bloodstream (on protein electrophoresis or light chain
determination), binding of particular antibodies to the
amyloid found in the tissue.

Treatment



Chemotherapy is the first line treatment in AL with

nephalan plus dexamethasone.



In AA, symptoms may improve if the underlying

condition is treated.



In familial causes of amyloidosis, a liver transplant can be

curative.