Immunologia of joint diseases

* Immunological of rheumatic diseases

Badr Qasem

• Selective migration of cells • Impaired apoptosis• Change function of cells T,B & APC• Dysruglation cytokine production• Autoimmunization

The etiology of rheumatic diseases

Immunological of rheumatic diseases

1- Factors

4-Effects

A. Exogenous : infection bacteria and viruses ?B. Endogenous : HLA haplotype

2- Break immune Auto-tolarnce

3- Disorders

• Polyclonal lymphocyte activation B & T

• Cross-reactivity• Release of auto-antigens

1- Inflammatory 2- Damage tissue

3- generalized symptoms

Diseases Factors

1- Septic arthritis local inflammatory

bacteria or viruses

2- Treponemal arthritis Borelie burgdorferi

3- Acute polyarthritis Parvovirus B19

4- Spondyloarthropathies - Bacteria infection (gastrointestinal)Shigella,Campylobacter,Yersiniaand Salmonella), (urogenital tract) Chlamydia trachomatis

5- Presence in synovial fluid TCD4+ lymphocytes

Responding to anti- Klebsiella IgA in serum of patients which indicate presence of infection enterobacter may play role in inducing rheumatic diseases.

6- Immune – complexes -In many of rheumatoid diseases(Rheumatic arthritis or Systemic Lupus Erythematous-SLE)

The role of infection factors in rheumatic diseases




Why consequence of different infections in distant organs and tissues comes to joints

inflammatory ?



Blood

Joints

Glycoprotein bone

Collagen type I

Adhesion protein Yad A

Staphylococcus aureus

YersiniaVirulence strains

- Phagocytic cells- Immune- complexes

- Notes : - In cells of synovial fluid reveal some RNA sequences derived from endogenous retroviruses in RA and JCA which suggested retroviral infection may play a role in the pathogenesis of autoimmune rheumatic disease

Diversity of Rheumatologic Diseases:

Common and Uncommon Diseases Involving Inflammatory and Immune

Responses

- Rheumatoid Arthritis*- Systemic Lupus Erythematosus*- Spondyloarthropathies*

Ankylosing spondylitisReactive Arthritis (Reiter’s

Syndrome)Psoriatic ArthritisSpondylitis associated with IBD

- Sjogren’s Syndrome- Polymositis/Dematomyositis- Lyme Disease- Rheumatic Fever- Behcet’s Syndrome- Systemic Sclerosis (Scleroderma)- Wegener’s Granulomatosis- Giant Cell Arteritis*

Immunologically-Mediated Diseases

(adaptive immunity)- Osteoarthritis*- Gout*- Pseudogout

Inflammatory Diseases (innate immunity)

Immunological joint diseases

Immune disorders


Inflammatory cascade

NOXIOUS STIMULI(Injury or Infection)

INNATE(immunologically non-

specific)

ADAPTIVE(immunologically specific)

VASCULAR EVENTS CELLULAR EVENTSANTIBODY MEDIATED

RESPONSECELL MEDIATED

RESPONSE

MICROSCOPICLEVEL

PRODUCTION OF NUMBEROUS CHEMICAL MEDIATORSAUTOCOIDS (Greek: autos “self” and akos “medical agent or remedy”PARACRINE SECRETIONS OR LOCAL HORMONES

Neurotransmitters Hormones• REDDENED • HOT

• SWOLLEN • PAINFUL• INTERFERENCE

FIBRINOLYTIC CASCADE

COAGULATION CASCADE

KININ CASCADE

COMPLEMENT CASCADE

CELLS ALREADY PRESENT1. Vascular endothelial2. Mast3. Tissue macrophages

CELLS ENTERINGTHROUGH BLOOD1. Platelets2. Leukocytes

INDUCTION PHASE

EFFECTOR PHASE

MACROSCOPIC LEVEL

Immune disorders


Immune disorders

normal joint (a) Joint affected by RA (b)

shows increased inflammation

and cellular activity

Cytokines


Immune disorders


Immune disorders

Proinflammatory

TNF- IL-8

IL-1 IFN-

IL-2 LT

IL-6 GM-CSF

Anti-inflammatory

IL-4

IL-10 sIL-1R

IL-11IL-1Ra

TGF- IL-13

sTNFR

Cytokine Disequilibrium in the disease Process of Rheumatic diseases


Immune disorders

CytokinesPro-

inflammatory

Source function

Immunological Related with joint diseases

TNF- Monocytes/macrophages, synviocytes A >B

Supporting:- Proliferation of T & B

cells- Differentiation of B

cells - Cytotoxicity NK

Inducing:- - Production pro-inflammatory

cytokines - Expression of adhesion molecules- Production metalloproteinase and

PGE- Resorption & synthesis of

proteoglycan

IL- 1 Monocytes/macrophages, synviocytes A >B

Supporting:- Activation of T & B cells- Secretion cytokines

Th1- Cytotoxicity NK

Inducing:- - Production pro-inflammatory

cytokines - Expression of adhesion molecules- Production metalloproteinase and

PGE- synthesis of collagens- Osteoclasts activation- The main factor of pyretic

IL- 6 Monocytes/macrophages, synviocytes A >B

Increasing:- Production IL-2- Production antibodies

Supporting:- Production metalloproteinase and

PGE- Main factor induction phase acute

response - Inducing production sTNFR , IL-1Ra

metalloproteinase inhibitor.- Decreases production of IL-1 & TNF-

IL- 8 Monocytes/macrophages, Neutrophils ,synviocytes A &B

- Chemotactic factor For neutrophils & lymphocytes- Neutrophils activation

- Like immunological function- Main factor for inducing

angiogenesis

GM- CSF Monocytes/macrophages, synviocytes A >B

Neutrophils & macrophage activation

- Like immunological function


Immune disorders

Cytokines Pro-inflammatory

TNF-α

TNF-α : play as central role which inducing the production of IL-1 , and both cytokines following the production of pro-inflammatory cytokines

TNF-α & IL-1

Synoviocytes B & A

Prostaglandins E2 (PGE2)

a series of metalloproteinase

Synovial fluid and synovium

Degradation of cartilage

TNF-α , IL-6 and IL-1β

Acute phase response

TNF-a & IL-1

In liver

- Acute phase protein like complement components

- Protein coagulation proteases inhibitors

IL-6

- Cross-reactive protein (CRP)

- Serum amyloid A (SAA)

- Anti-trypsin or fibrinogen

Collagenase stromielizinesgelatinizes

TNF-α & IL-6

Synergistic manner

Destruction

of joint tissues

production

production

- Increase activation of MØ

- stimulation production IL-1β and TNF-α

Large amount presence in synovial fluid

Immune disorders Cytokines

- Production of collagenase by synoviocytes B

- Increase expression of adhesion molecules monocytes & neutrophils

Large amount presence in synovial fluid

Cytokines Pro-inflammatory


Proinflammatory

IL-6, IL-8, GM-CSFIL-1

TNF

Anti-inflammatory

IL-10, sTNFR, IL-1Ra,

Inflammation

Activates monocytes/macrophages

Bone resorption and erosions

Activates osteoclasts, suppresses osteoblasts

Cartilage breakdown

Activates chondrocytes,

releasing collagenases

TNF



CytokinesAnti-

inflammatory

Source function

Immunological Related with joint diseases

IL- 4 Th2 cells Stimulation :- Differentiation of T & B cells- Decreases production pro-

inflammatory cytokines

- Decreases as immunological function

- Production metalloproteinase

IL- 10 T lymphocytessynviocytes A

- Stimulation Th2 cells - Decreases Proliferation Th1- Activation macrophages &

production by not cytokines


IL- 13 - Stimulation differentiation B cells

- Decreases production pro-inflammatory cytokines


TGF-β Different cells - Decreases development and production cytokines by T cells

- Development and Differentiation of B cells

- Stop effect TNF-

- Like immunological function- Inducing production of tissues

inhibitors metalloproteinase- Supporting production collagen &

tissues repair processes

sTNF- R Different cells - Binding TNF- & neutralize it s effect


IL- 1Ra Different cells - Blocking binding IL-1 to receptor & stopping their biological effect



The major of cytokines anti-inflammatory

IL-10 TGF-B IL-4 IL-13

Lymphocytes /macrophage

Various types of cells

Th1 chemokine's

Th lymphocytes/m

ast cells /NK cells

Anti-inflammatory action for IL-6 & TNF-

α

The main action of anti-inflammatory cytokines

IL-4,IL-13,IL-10 & TGF-β

Ability to inhibition pro-inflammatory

cytokines

Increase production of IL-1Ra

Has a strong immunosuppression effect

Blocking proliferation and activation lymphocytes



In clinical course

Juvenile chronic arthritis (JCA)

High concentration of IL-6 in serum & synovial fluid

Anima

Impaired growth

Amyliodosis

osteoporosis

TNF-α Appear in vary important development of systemic symptoms ( fever , disorders of coagulation

Selective migration of immunological cells to

inflamed joints


Immune disorders

normal joint (a) Joint affected by RA (b)

shows increased inflammation

and cellular activity


Immune disorders


Immune disorders

The multi-step paradigm of leukocyte migration: Step 1: Tethering & rolling

Cytokine (pro inflammatory cytokines )activated endothelial cells express adhesion molecules Leukocytes ‘marginate’ from the peripheral pool to the marginal pool

Tethering and rolling are mediated by SELECTINS and ADDRESSINS

Tethering4000 microns/sec

Rolling40 microns/sec


Immune disorders

Neutrophilis activated

bychemokine's

IL-8

Selecting is shedRolling

Cytokines from endothelial activate expression of Intracellular adhesion molecules (ICAMs)

INTEGRIN (adhesion molecule) has low affinity for ICAM

Cell activation changes integrin to high affinity

format

Steps 2 & 3: Activation & arrest

Presence both molecules has significant increase in RA

Integrin

IntegrinsTwo chain molecules - that bind to Ig superfamilymolecules and extracellular matrix components

INTEGRIN Ig FAMILY LIGANDaLb2 (LFA-1) ICAM-1

Ig family ligand

Activation of lymphocyte

increases affinity of integrin(Mn2+ in vitro)


Immune disorders

Step 4:Migration and diapedesis

Firm adhesion causes the leukocyte to flatten and migrate between the endothelial cells

Leukocyte migrates towards site of infection by detecting and following a gradient of chemokine.

Leukocytes migrate readily to the chemokine RANTES which synthesis by MØ , endothelial cells and synovial fibroblast

~10 Minutes


Immune disorders

Disorders of apoptosis


Immune disorders

apoptosis

Some studies that observed that apoptosis may contribute of development of autoimmune diseases including RA

Also with patients wit rheumatic diseases they shown us more complex picture of peripheral blood lymphocytes with SLE

By increasing spontaneous apoptotic death which suggested as a result that by enhance a apoptosis cells

Apoptosis of synoviocytes B may be responding for expansion in the synovium

Cytokines play role against apoptosis of synoviocytes

IL-1β

TGF- β

Inhibition apoptosis cells by inducing Fas/FasL

Reduce in these cells expression Fas and increase of expression Bcl-2 and proliferation cells


Immune disorders


Immune disorders

Antigen presenting cells

IL-6 & others enzymes degradation

Hyperplasia

IL-8 & othersInflammatory

mediators

Ab, AutoAb,Immune-complex

TNF,IL-1 & other enzymatic degradation

Inflammatory mediators

The influx and cell activation and cytokine production

Synoviocytes BneutrophilLymphocyte BSynoviocytes A

Factor inducing ( damage tissues , inflammation

Maturation of DCs - APCs function , migration DCs

joint

Chro

nic

Acu

teIn

itia

tion

joint

Sensitization of T cells( including auto reactive)

Local cytokine production

Phenomena

Memory T cells migration and thier activation

Location

Lymph nods

joint

joint

Lymph nods

Phase of diseases

The etiopathogenesis of rheumatic diseases hypothesis about the key role of DCs


Immune disorders

T Lymphocytes

IL-6 & others enzymes degradation

Hyperplasia

IL-8 & othersInflammatory

mediators

Ab, AutoAb,Immune-complex

TNF,IL-1 & other enzymatic degradation

Inflammatory mediators

The influx and cell activation and cytokine production

Synoviocytes BneutrophilLymphocyte BSynoviocytes A

Factor inducing ( damage tissues , inflammation

The influx and their activation + cytokine production inflammation⟶

joint

Chro

nic

Acu

teIn

itia

tion

joint

Sensitization of auto reactivation T cells

Sensitization of T cells

Phenomena

Migration of autoreactivation T cells memory & their activity by APCs

Location

Lymph nods

joint

joint

Phase of diseases

The etiopathogenesis of rheumatic diseases hypothesis about the central role of T lymphocytes

Migration of memory T cells

Activation of T cells by APCs

Release own antigen + APCs

Lymph nods

joint


Immune disorders


Immune disorders

B Lymphocytes

B- Lymphocytes

binding to citrullinated proteins located in the cellular membrane

binding to FcγIIIa receptors

bound to other cellular receptors (such as TLR4)

The inflamed rheumatoid synovial membrane and fluid are a reservoir of activated immune cells and locally produced antibodies

a high proportion of the synovial IgG -expressing cells (memory and early plasma blasts)


Immune disorders

Neutrophil


Immune disorders


Immune disorders


Immune disorders

Synoviocytes type B


Immune disorders

This cells are fibroblasts and/or fibroblast-like cells that are found between the cartilaginous fibers in the synovial membrane of joints

secrete a variety of effector molecules that promote inflammation and joint destruction and, themselves are part of a complex network

of autocrine and paracrine acting factors

Doesn’t belong to immune cells but they have number of properties that make it play a vary important role in immunopathogensis of joint diseases

The best function in Rheumatic diseases they are fibroblast synthesis a protein constituting a connective tissues e.x. proteoglycan

In the presences of proinflammatory cytokines such as TNF-a and IL-1 this cells start produce numerous enzymes degrading the extracellular matrix protein (serine ,

protease , cathepsin and metalloproteinase)

In the case of patients with rheumatic diseases is predominant inhibitors of metalloproteinase(in degeneration joint diseases) which make this cells contribute to

destructive processes

This cells are also supporting the cytokine network with presence TNF-a & IL-1 start producing cytokines pro-inflammatory (IL-6,IL_8 and GM-CSF) & FGF


Immune disorders

Thank you for your attention

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Immunologia of joint diseases