Session 10:Chronic Inflammation

Session 10:Chronic Inflammation

• Alex Simon (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Define chronic inflammation.

Identify causes of chronic inflammation.

Explain morphological features of chronic inflammation.

Explain types of chronic inflammation.

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Definition

Definition

Chronic inflammation is inflammation of prolonged duration (weeks to years) in which continuing inflammation, tissue injury, and healing often by fibrosis, proceed simultaneously.

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Causes of Chronic Inflammation

Causes of Chronic Inflammation

Chronic inflammation following acute inflammation.

Recurrent attacks of acute inflammation.

Chronic inflammation starting from agents known to cause chronic inflammatory response.

Persistent infections by microbes that are difficult to eradicate.

Immune-mediated inflammatory diseases (hypersensitivity and autoimmune diseases).

Prolonged exposure to potentially toxic agents.

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Morphological features of Chronic inflammation

Morphological features of Chronic inflammation

Chronic inflammation is characterized by a different set of reactions

Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells.

Tissue destruction, largely induced by the products of the inflammatory cells.

Repair (healing by fibrosis), involving new vessel proliferation (angiogenesis) and fibrosis.

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Chronic inflammatory cells and mediators

Chronic inflammatory cells and mediators

Chronic inflammation involves complex interactions between several cells population and their secreted mediator.

These chronic inflammatory cells mainly include macrophages, lymphocytes, plasma cells, mast cells, eosinophils.

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Macrophages

Macrophages

Dominant cells of chronic inflammation.

Derived from circulating blood monocytes.

Diffusely scattered in most connective tissues.

They are also found in organs such as

Liver (Kupffer cells)

Spleen and lymph nodes (sinus histiocytes)

CNS (microglial cells)

Lungs (alveolar macrophages)

Langerhans’ cells/dendritic histiocytes (skin)

Forming mononuclear phagocyte system (reticuloendothelial system).

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Macrophages

Macrophages

Monocytes arise from precursors in the bone marrow and circulate in the blood for only about a day.

They migrate to a site of injury within 24 to 48 hours after the onset of acute inflammation.

Under the influence of adhesion molecules and chemokines.

When monocytes reach the extravascular tissue, they undergo transformation into macrophages.

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Macrophages

Macrophages

Macrophages are larger and have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes.

In all tissues, macrophages

Act as filters for particulate matter, microbes, and senescent .

Effector cells that eliminate microbes in cellular and humoral immune responses.

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Macrophages activation

Macrophages activation

Tissue macrophages are activated by diverse stimuli to perform a range of functions.

There are two (2) major pathways of macrophage activation

Classical pathway.

Alternative pathway.

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Classical macrophage activation

Classical macrophage activation

Classical macrophage activation is induced by

Microbial products such as endotoxin.

T cell–derived signals, importantly the cytokine Interferon gamma (IFN-γ).

Foreign substances including crystals and particulate matter.

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Classical macrophage activation

Classical macrophage activation

Activated macrophages secrete cytokines that stimulate inflammation.

Those cytokines are interleukin-1 (IL-1), interleukin-12 (IL-12), interleukin-23 (IL-23) and chemokines.

These activated macrophages are important in host defense against ingested microbes and in many chronic inflammatory reactions.

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Classical macrophage activation

Classical macrophage activation

Classically activated macrophages produce

Lysosomal enzymes.

Nitric oxide.

Reactive oxygen species.

Those above products enhance activated macrophages the ability to kill ingested organisms.

Thus classically activated macrophages are microbicidal.

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Alternative macrophage activation

Alternative macrophage activation

Alternative macrophage activation is induced by cytokines such as interleukin-4 (IL-4) and interleukin-12 (IL-13)

Those interleukins are produced by T lymphocytes and other cells, including mast cells and eosinophils.

Alternative activated macrophages have principal role is in tissue repair.

They are not actively microbicidal.

They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis (in tissue repair).

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Activity: Brainstorming

Activity: Brainstorming

What are the roles of macrophages in host defense and inflammatory response?

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Roles of macrophages in host defense and inflammatory response

Roles of macrophages in host defense and inflammatory response

Macrophages ingest and eliminate microbes and dead tissues.

Macrophages secrete chemical mediators of inflammation.

Macrophages initiate the process of tissue repair and are involved in scar formation and fibrosis (in alternative activation pathway).

Macrophages display antigens to T lymphocytes and respond to signals from T cells (bidirectional interactions).

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Macrophages

Macrophages

After the initiating stimulus is eliminated and the inflammatory reaction abates, macrophages eventually die or wander off into lymphatics.

In chronic inflammatory sites, however, macrophage accumulation persists, because of continued recruitment from the blood and local proliferation.

Interferon gamma (IFN-γ) can also induce macrophages to fuse into large, multinucleate giant cells.

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Lymphocytes

Lymphocytes

Lymphocytes are mobilized in the setting of

Specific immune stimulus (in infections)

Non–immune mediated inflammation (due to ischemic necrosis or trauma).

These are the major drivers of inflammation in many autoimmune and other chronic inflammatory diseases.

The activation of T and B lymphocytes is part of the adaptive immune response.

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Lymphocytes cont…

Lymphocytes cont…

Lymphocytes migrate into inflammatory sites using some of the same adhesion molecule pairs and chemokines that recruit other leukocytes.

In the tissues

B lymphocytes may develop into plasma cells, which secrete antibodies

CD4+ T lymphocytes are activated to secrete cytokines thus these cells promote inflammation and influence the nature of the inflammatory reaction.

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Lymphocytes cont…

Lymphocytes cont…

There are three (3) subsets of CD4+ helper T cells that secrete different sets of cytokines and elicit different types of inflammation:

CD4+ helper T cells 1 (TH1).

CD4+ helper T cells 2 (TH2).

CD4+ helper T cells 17 (TH17).

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Subsets of CD4+ helper T cells cytokines produced

Subsets of CD4+ helper T cells cytokines produced

TH1 cells produce the cytokine IFN-γ

Activates macrophages in the classical pathway.

TH2 cells secrete interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13).

Recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.

TH17 cells secrete interleukin-17 (IL-17) and other cytokines that induce chemokines.

Recruiting neutrophils and monocytes into the reaction.

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Subsets of CD4+ helper T cells cont…

Subsets of CD4+ helper T cells cont…

Both CD4+ helper T cells 1 (TH1) and CD4+ helper T cells 17 (TH17) cells are involved in defense against:

Bacteria.

Viruses.

Autoimmune diseases.

CD4+ helper T cells 2 (TH2)cells are important in defense against

Helminthic parasitic infestations.

Allergic inflammation.

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Lymphocytes and macrophages interaction

Lymphocytes and macrophages interaction

Lymphocytes and macrophages interact in a bidirectional way thus propagating chronic inflammation.

Macrophages display antigens to T cells, express membrane molecules and produce cytokines (interleukin-12 (IL-12) and others) that stimulate T cell responses.

Activated T lymphocytes, in turn, produce cytokines, which recruit and activate macrophages and thus promote more antigen presentations and cytokine secretions.

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Lymphocytes and macrophages interaction

Lymphocytes and macrophages interaction

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Eosinophils

Eosinophils

These are characteristically found in inflammatory sites in

Parasitic infections.

Allergic reactions.

Eosinophils is recruited by adhesion molecules of neutrophils and chemokines e.g. eotaxin.

Eosinophil granules contain major basic protein that is toxic to parasites but also causes epithelial cell necrosis.

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Mast cells

Mast cells

In atopic persons (those prone to allergic reactions), mast cells are “armed” with IgE antibody specific for certain environmental antigens (allergens).

When these antigens are subsequently encountered, the IgE-coated mast cells are triggered to release histamines and arachidonic acid metabolites that elicit the early vascular changes of acute inflammation.

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Neutrophils

Neutrophils

Although the presence of neutrophils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to show extensive neutrophilic infiltrates,

Due to either persistent microbes or necrotic cells, or mediators elaborated by macrophages.

Such inflammatory lesions are sometimes called “acute on chronic”—for example, in inflammation of bones (osteomyelitis).

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Tissue destruction or Necrosis

Tissue destruction or Necrosis

Tissue destruction and necrosis are the central features of most forms of chronic inflammatory lesions.

This is caused by activated macrophages which release a variety of biologically active substances:

Enzymes (protease, elastase, collagenase, lipase).

Reactive oxygen species.

Cytokines (interleukin-1 [IL-1], interleukin-8 [IL-8], tumour necrosis factor [TNF]).

Nitric oxide.

Angiogenesis and growth factor.

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Proliferative changes

Proliferative changes

As a result of necrosis, proliferation of small blood vessels and fibroblasts is stimulated.

This resulting in formation of inflammatory granulation tissue, whose end result is healing by fibrosis and collagen laying takes place.

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Types of Chronic inflammation

Types of Chronic inflammation

Chronic inflammation can be classified into the following two (2) types based on histologic features:

Chronic non specific inflammation.

Chronic granulomatous inflammation.

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Chronic non-specific inflammation

Chronic non-specific inflammation

It is characterised by non-specific inflammatory cell infiltration (macrophages and lymphocytes) such as in chronic osteomyelitis and lung abscess.

Occurs when the irritant substance produces a nonspecific chronic inflammatory reaction with formation of granulation tissue and healing by fibrosis e.g. chronic osteomyelitis, chronic ulcer.

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Chronic granulomatous inflammation

Chronic granulomatous inflammation

It is a distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages with scattered lymphocytes.

Granulomas are circumscribed, tiny lesion, about 1 mm in diameter.

Composed predominantly of collection of modified macrophages (activated macrophages) called epithelioid cells and rimmed at the periphery by lymphoid cells (lymphocytes).

Epithelioid cells resemblance to epithelia in appearance.

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Granuloma

Granuloma

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Granuloma formation

Granuloma formation

The formation of a granuloma effectively “walls off” the offending agent and is therefore a useful defense mechanism.

However, granuloma formation does not always lead to eradication of the causal agent, which is frequently resistant to killing or degradation

Thus granulomatous inflammation with subsequent fibrosis may even be the major cause of organ dysfunction in some diseases such as tuberculosis.

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Granulomas can form under the following settings:

Granulomas can form under the following settings

With persistent T-cell responses to certain microbes as in TB.

Granulomas may develop in some immune- mediated inflammatory diseases, e.g. Crohn disease.

They develop in response to relatively inert foreign bodies (e.g., suture or splinter) forming foreign body granulomas.

Granulomas are also seen in a disease of unknown etiology e.g. in sarcoidosis

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Morphology of granuloma

Morphology of granuloma

In the usual H&E preparations, some of the activated macrophages in granulomas have pink, granular cytoplasm with indistinct cell boundaries.

Aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes.

Older granulomas may have a rim of fibroblasts and connective tissue.

Besides the presence of epithelioid cells, granulomas may have multinucleated giant cells, necrosis and fibrosis.

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Diseases with granulomatous inflammation

Diseases with granulomatous inflammation

Bacterial: Tuberculosis, Syphilis, Leprosy, Cat scratch disease, Plague.

Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis.

Helminthic: Schistosomiasis.

Protozoal: Leishmaniasis, Toxoplasmosis.

Chlamydia: Lymphogranuloma venerum.

Inorganic material: Berrylliosis, Silicosis.

Immunological: Crohn’s disease.

Idiopathic: Sarcoidosis.

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Key points

Key points

Chronic inflammation is a prolonged host response to persistent stimulus.

It is caused by microbes that resist elimination, immune responses against self and environmental antigens, and some toxic substances (e.g., silica)

It is characterized by persistent inflammation, tissue injury, attempted repair by scarring.

Cellular infiltrate consisting of activated macrophages, lymphocytes, and plasma cells.

Mediated by cytokines produced by macrophages and lymphocytes (notably T lymphocytes).

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Review questions

Review questions

Explain how lymphocytes and macrophages interaction fueling chronic inflammation.

How tissue destruction and necrosis are the occurs in chronic inflammatory reaction?

List two (2) factors favour proliferative changes in chronic inflammatory reaction

What are the components of granuloma?

List three (3) settings which favour granuloma formation.

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References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 35-38.

Kumar V.; Abbas A. K.; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, China. Pg. 53-57.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India . Pg. 141-144, 147-149.

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