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IMMUNE COMPLEX DISEASES

PRESENTED BY: KARANJA STEPHEN MBUGUA

MBCHB LEVEL 3

SUPERVISOR: DR.GONTIER

QUESTION

What are the immune complex diseases? And discuss the

pathogenesis and principle features of one of these diseases.


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INTRODUCTION

DEFINITION

These are disease conditions that are brought about when antigen-antibody interaction occur

to form an immune complex and instead of being removed by the mononuclear phagocyte

system they persist and are deposited in various organs and tissues in the body.

It's a type 3 hypersensitivity reaction where circulating antibodies bind antigens to form an

immune complex in blood leading to systemic disease or form locally at specific sites such as

the lungs.

Immune complexes can trigger a variety of inflammatory processes:

(a) They interact directly with basophils and platelets via Fc receptor interaction to induce

release of vasoactive amines.

(b) Macrophages are stimulated to release cytokines, particularly TNF-alpha and IL-1

(c) They interact with the complement system to generate C3a and C5a (anaphylatoxins) that

stimulate release of vasoactive amines and act as chemotactic factors to mast cells and

WBCs

Diseases resulting from immune complex formation and deposition are divided into 3

groups:

(a) Those due to persistent infection

(b) Those due to autoimmunity

(c) Those caused by inhalation of antigenic material

1. THOSE DUE TO PERSISTENT INFECTIONS

The combined effects of a low-grade persistent infection and weak Ab response lead to

chronic immune complex formation and there deposition in the tissues.


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EXAMPLES

Leprosy

Malaria

Dengue hemorrhagic fever

Viral hepatitis

Staphylococcal infective endocarditis

Trypanosomiasis

2. THOSE DUE TO AUTOIMMUNITY

When there is production of antibodies towards self-antigens in the body it leads to prolonged

immune complex formation.

As the immune complexes in blood increase, the systems responsible for their removal

(mononuclear phagocyte, erythrocyte and complement) become overloaded and the

complexes are deposited in the tissues.

EXAMPLES

Rheumatoid Arthritis (RA)

Systemic Lupus Erythematous (SLE)

Polymyositis

Sjogren's syndrome (SS)

Progressive Systemic Sclerosis (PSS)

Mixed Connective Tissue Disease (MCTD)

Polyarteritis Nodosa (PAN)

Glomerulonephritis (GN)

3. THOSE DUE TO INHALATION OF ANTIGEN (EXTRINSIC ANTIGENS)

It occurs following repeated inhalation of antigenic materials from molds, plants or animals.

When these antigens enter the lungs and induce an immune reaction, local immune

complexes form in the alveoli leading to inflammation and fibrosis.


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NOTE: The antibodies induced by these antigens are primarily IgG and not IgE seen in type 1

hypersensitivity reaction.

EXAMPLES

Farmer's lung, where there are circulating Abs to actinomycete fungi.

Pigeon fancier's lung, where there circulating Abs to pigeon antigens (specifically pigeon

droppings)

OVERVIEW

OVERVIEW 2

RHEUMATOID ARTHRITIS


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INTRODUCTION

It's a chronic systemic inflammatory disorder that may affect many tissues and organs-skin,

blood vessels, heart, lungs and muscles-but it principally attacks the joints, producing non

suppurative proliferative and inflammatory synovitis that often progresses to articular cartilage

destruction and ankylosis of the joints.

Cause is still unknown, but genetic predisposition, environment and autoimmunity have a

pivotal role in development, progression and chronicity of the disease.

About 1% of the worlds population has rheumatoid arthritis.

Women are 3/5 times more likely to developed it as compared to men,

It's common in those people between 40-70 years but no age is immune.

MORPHOLOGY

JOINTS.

The most severe manifestations of the morphological alterations due to rheumatoid arthritis

are seen in the joints.

Initially: synovium becomes grossly edematous, thickened and hyperplastic, transforming

its smooth contour to one covered by delicate and bulbous fronds.

Histologically: (1) infiltration of synovial stroma by a dense perivascular inflammatory

infiltrates, specifically CD4+ helper T cells, B cells, plasma cells, dendritic cells and

macrophages.

(2) Increase vascularity due to vasodilation and angiogenesis, with hemosiderin

deposits.

(3) Aggregation of organized fibrin covering portions of the synovium and floating

in the joint space (rice bodies).

(4) Neutrophil accumulation in the synovial fluid and along the surface of the

synovium.

(5) Osteoclastic activity in underlying bone causes the synovium to enter the

bone and cause juxta-articular erosion, subchondrol cyst and osteoporosis.

(6) Pannus formation. It's a mass of synovium and synovial stroma consisting of inflammatory


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cells, granulation tissue and synovial fibroblasts that grow over articular cartilage and causes

its erosion

.

SKIN.RHEUMATOID NODULES

Are cutaneous lesions that occur in 25% of RA patients?

Occur in areas subjected to pressure such as ulnar aspect of the forearm, elbows, occiput

and lumbosacral area.

The nodules also occur rarely in the lungs, spleen, pericardium, myocardium, heart valves,

aorta and other viscera.

Grossly: Firm, non-tender and round to oval.

Histologically: central zone of fibrinoid necrosis surrounded by a prominent rim of activated

macrophages (epitheliod histiocytes) and lymphocytes and plasma cells.

BLOOD VESSELS

It's basically rheumatoid vasculitis that occurs as a complication on rheumatoid arthritis.

It affects patients with severe erosive disease, rheumatoid nodules and high titers of

rheumatoid factor.

It affects medium-small sized arteries similar to that occurring in Polyarteritis Nodosa (PAN)

except in RA the kidneys are not involved.

Segments of small arteries such as the vasa nervorum and digital arteries are obstructed by

an obliterating endarteritis resulting in peripheral neuropathy, ulcers and gangrene.

Leukocytoclastic venulitis produces purpura, cutaneous ulcers and nail beds infarction.

Rheumatoid arthritis


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Subcutaneous rheumatoid nodule with an area of necrosis (top) surrounded by macrophages

and scattered chronic inflammatory cells

PATHOGENESIS

It is believed that rheumatoid arthritis is triggered by exposure of a genetically susceptible

host to an arthritogenic antigen resulting in breakdown of immunological self-tolerance and

chronic inflammatory reaction.

Thus, acute arthritis is initiated, but it is the continuing autoimmune reaction, activation of

CD4+ helper T cells and local release of inflammatory mediators and cytokines that ultimately

destroy the joint.

GENETIC SUSCEPTIBILITY

It's a major contributor to the pathogenesis of RA.

Specific HLA-DRB1 alleles is believed to be associated with RA, in that these alleles share a

common AA sequence in the 3rd hyper variable region of the beta chain, which is designated

the shared epitope.


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This epitope is located on the DR molecule and is the one that bind the arthritogen (s) that

initiates inflammatory synovitis.

Another gene is the PTPN22; it encoded protein tyrosine phosphatase, which participates in

activation and control of inflammatory cells (including T cells)

ENVIROMENTAL ARTHRITOGENS

It is still uncertain as to whether these arthritogens initiate the disease.

Microbial agents include: Epstein-Barr virus, retroviruses, parvoviruses, mycobacteria,

Borrelia, Proteus mirabilis and mycoplasma.

Recently, citrullinated proteins (proteins modified by enzymatic conversion of arginine to

citrulline), many of which are fibrins formed in the body (especially in the lungs of smokers)

are implicated in RA pathogenesis.

The immune reaction to these auto antigens suggests they are an important potential

arthritogenic agent.

AUTOIMMUNITY

Once inflammatory synovitis has initiated an autoimmune reaction (where T cells play a

pivotal role) is responsible for the chronic destruction in RA.

Activated CD4+ effector and memory T cells appear within the joint early in disease.

TH17 cells are also present and they recruit neutrophils and monocytes.

TH1 cells which are present as well produce INF-gamma that also contributes to inflammation

80% of patients with RA have circulating auto Abs to the Fc portion of autologous IgG

(rheumatoid factor). These are mostly IgM Abs but may be of other classes or self-associated

(RA-IgG) to form immune complexes in the sera, synovial fluid and synovial membrane.

Antibodies to citrulline-modified peptides (anti-cyclic citrullinated peptide [CCP] Abs) are

common in patients with RA but rare in other inflammatory diseases or healthy people.

Evidence suggests that the raised level of anti-CCP Abs and T cell response to the

citrullinated proteins contribute to the disease being chronic.

Mediators that bring about the destructive proliferative synovitis are: Cytokines secreted by T

cells, such as INF- gamma and IL-17 which stimulate synoviocytes and macrophages to

produce pro-inflammatory molecules such as IL-1, IL-6, IL-23, TNF, PGE2, NO, growth factors


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granulocyte-macrophage colony-stimulating factor and TGF-beta.

They activate endothelial cells in the synovium thus facilitate leukocyte binding and

transmission.

They also cause increased production ofcartilage matrix metalloproteinases, which along

with Ag-Ab complexes cause destruction of the articular cartilage.

They are also potent stimulators of osteoclastogenesis and osteoclast activity by up-

regulating production of RANKL (which is also expressed in T cells and activated

synoviocytes)

The edematous, hyperplastic and sticky (synoviocytes up-regulate vascular cell adhesion

molecule) synovium rich in inflammatory cells becomes adherent to and grows over the

articular surface forming a pannus and stimulate resorption of adjacent bone.

In time after the cartilage has been destroyed, the pannus bridges the opposing bone forming

fibrous ankylosis which eventually ossifies and results in bony ankylosis. Inflammation of

the tendons, ligaments and at times adjacent skeletal muscles accompanies the arthritis.

Only TNF has been firmly implicated in pathogenesis of RA and TNF antagonists have been

developed and are effective in arresting disease progression with relieve of pain and swelling

SUMMARY OF THE PATHOGENESIS

CLINICAL FEATURES

In more the 50% of RA patients the disease is slow and insidious.


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Its progression is extremely variable.

Early feature: malaise, fatigue and generalized musculoskeletal pain, only after several

weeks do the joints get involved.

Pattern of join involvement varies but commonly it begins by affecting the small joints first

(metacarpophalangeal and proximal interphalangeal joints) and feet, followed by wrists,

ankles, elbows, and knees

Involved joints are: swollen, warm, painful and stiff following inactivity.

Radiographic hallmarks: joint effusions and juxta-articular osteopenia with erosion and

narrowing of joint space with loss of articular cartilage.

Tendon, ligament and joint capsule destruction produce characteristic deformities; radial

deviation of the wrist, ulnar deviation of the fingers and flexion-hyperextension abnormalities

of the fingers (swan neck, boutonniere).

DIAGNOSTIC FEATURES

It includes the presence of four of the following criteria:

(a) Morning stiffness

(b) Arthritis in 3 or more joint areas

(c) Arthritis of hand joints

(d) Symmetric arthritis

(e) Rheumatoid nodules

(f) Serum rheumatoid factor

(g) Typical radiographic changes


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TREATMENT

Corticosteroids

Synthetic and biological disease-modifying drugs e.g. methotrexate and TNF antagonist.

NB: (1) Treatment with anti-TNF and other immunosuppressive drugs are not curative and

patient must maintain course of treatment to avoid disease flares.

(2)Patients on anti-TNF are susceptible to certain infections, particularly M.tuberculosis

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