pathogenesis systemic lupus erythematosus by dr bashir ahmed dar associate professor medicine sopore...

8/8/2019 Pathogenesis Systemic Lupus Erythematosus by Dr Bashir Ahmed Dar Associate Professor Medicine Sopore Kashmir

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Systemic Lupus Erythematosus

By Dr Bashir Ahmed Dar

Associate Professor of MedicineChinkipora Sopore Kashmir

Email-- [email protected]



Dr Bashir and Dr yashodhora leading group of medical students tomeet noble prize winner in medicine at KL Malaysia



P recious moments with noble prize winner



Dr Bashir at PBL Conference



M y Son Yawer Bashir



M y Home in Kashmir



SLE is an autoimmune inflammatory diseaseinvolving multisystem or multiorgans of thebody .




Basically, in autoimmune diseases, the humanimmune system wrongly recognizes tissues of the body as harmful antigens and so builds aresponse, targeting self-cells .



Background on Systemic LupusErythematosus

Lupus is Latin for wolf, and "erythro" isderived from Greek for "red .




In various accounts, some doctors thought therash resembled the pattern of fur on a wolf'sface .




In other accounts,doctors thought thatthe rash, which was

often more severe inearlier centuries,created lesions thatresembled wolf bites

or scratches .




Another account claims that the term "lupus"did not come from Latin directly, but from theterm for a French style of mask that womenreportedly wore to conceal the rash on theirfaces . The mask is called a "loup," French for"wolf ."




The term lupus is attributed to 12th-centuryphysician Rogerius, who used it to describethe classic malar rash .

Useful medication for the disease was firstfound in 1894, when quinine was firstreported as an effective therapy .




Four years later, the use of salicylates inconjunction with quinine was noted to be of still greater benefit .

This was the best available treatment until themiddle of the twentieth century, when Henchdiscovered the efficacy of corticosteroids inthe treatment of SLE .




M ichael Jackson suffered from both SLE andvitiligo .D iagnosed in 1986, and confirmed byhis dermatologist, D r. Arnold Klein, whopresented legal documents during courtdepositions .




Lady Gaga has been tested borderline positivefor SLE, however she claims not to be affectedby the symptoms yet .Teddi King, Americansinger, died of SLE complications in




In 1977 Charles Kuralt, former anchor of CBSSunday M orning, died of SLE complications in1997 .Ferdinand M arcos, former P hilippinepresident, who died of SLE complications in1989 .




M illions of Americans are afflicted with anautoimmune disease, mostly women of childbearing age . Generally, autoimmunediseases are lifelong conditions, althoughmedication and treatment can make quality of life better for the patient .




P redominantly affects females at a rate of almost 9 to 1 .

Though disease can affect all ages but mostcommonly begins from 20-45 years of age .

Common in Hispanic and African-Americanwomen than in Caucasian women .

The disease occurs in 1 out of 2,000Americans and in as many as 1 out of 250African-American women .



Etiology

Heredity/ GeneticSex hormone statusEnvironmental triggers /Immunological factor sLoss of self-toleranceComplement deficiency



Heredity/ Genetic causes

The most important genes causing SLE arelocated in the HLA region on chromosome 6,where mutations may occur randomly or maybe inherited . HLA class I, class II, areassociated with SLE .




14 of the genes where linked to SLE patientsmanifesting a severe form of the disease .

The 14 genes are collectively referred to as theinterferon (or IFN) expression signature . Thegenes are turned on by interferon activity . IFNis a family of proteins that is involved inimmune response regulation .




The data show support for therapies thatwould block IFN pathways . This may be ableto help patients with a more severe form of the disease .




Genetic predispositionM HC genes: HLA D R2, D R3, D R4-D IL,D R5- AP SNon- M HC genes: complement component,complement receptor, Fc receptors, CR P, cytokines,apoptotic genes (e .g. , FAS)




Relatives of patients with autoimmune diseaseoften show high incidence of same type of auto-Ab .

And may have some form of autoimmunedisease .



BUT GENETIC PREDISPOSITION IS NOT ENOUGH ? NEEDENVIRONMENTAL FACTORS



Environmental Factors Causing SLE

These factors not only exacerbate existing SLE

conditions but also trigger the initial onset.




They include certain medications (such assome antidepressants and antibiotics),extreme stress, exposure to sunlight,hormones, and infections .




UV radiation has been shown to trigger thephotosensitive lupus rash and some evidencesuggests that UV light might be capable of altering the structure of the D NA, leading tothe creation of autoantibodies .




Researchers have sought to find a connectionbetween certain infectious agents (viruses andbacteria), but no pathogen can be consistentlylinked to the disease .




Some researchers have found that womenwith silicone gel-filled breast implants haveproduced antibodies to their own collagen,but it is not known how often theseantibodies occur in the general population,and there is no data that show that these

antibodies cause connective tissue diseasessuch as SLE . There is also a small but growingbody of evidence linking SLE to lipstick usage,




D rug-induced lupus erythematosus is a(generally) reversible condition that usuallyoccurs in people being treated for a long-termillness .




D rug-induced lupus mimics SLE . However,symptoms of drug-induced lupus generallydisappear once the medication that triggeredthe episode is stopped . There are about 400medications that can cause this condition, themost common of which are procainamide,

hydralazine, quinidine, and phenytoin .




Wide range of possible infection; somegenetic combinations result in autoimmunity . The likely environmental triggers includeultraviolet light, drugs, and viruses . Thesestimuli cause the destruction of cells andexpose their D NA, histones, and other

proteins, particularly parts of the cell nucleus .




Because of genetic variations in differentcomponents of the immune system, in somepeople the immune system attacks these

nuclear-related proteins and producesantibodies against them .

In the end, these antibody complexes damageblood vessels in critical areas of the body, suchas the glomeruli of the kidney; these antibodyattacks are the cause of SLE .




Researchers are now identifying the individualgenes, the proteins they produce, and theirrole in the immune system . Each protein is alink on the autoimmune chain, andresearchers are trying to find drugs to breakeach of those links .




D rugs such as hydralazine, methyldopa, andminocycline can induce lupus not associatedwith anti-ds D NA. D rug induced antibodies to histones .



Environmental Factors Causing SLE Even Provoking factors like

± Sunlight, UV light ± Infections ± Drugs

IsoniacidHidantoinHydralazinProcainamideD penicillinaminPenicillins

SulphonamidsTNF alpha blockersFlare-ups can be induced by the contraceptive pill and hormonereplacement therapy (HRT).



HORM ONAL FACTORS CAUSING SLE

Estrogen and other female hormones areconsidered to play a role since women aremore likely to be affected .

P rogesterone also have been shown to controlthe activity and production of MMP -9 .

Surprisingly,MMP

-9 activity in females did notcorrelate strongly with SLE, but did so in malepatients .




Testosterone reduces immunoglobulinproduction from peripheral blood as well asmononuclear cells of both normal subjectsand patients with SLE .

Improvement of SLE was noted in individualpatients who had undergone menopause orophorectomy .




Flares of SLE are well known to occur duringperiods of rapid hormonal changes . Theseinclude pregnancy, puerperium, ovulationstimulation during in vitro fertilisation, andexogenous oestrogen administration .




Lupus activity tends to be reduced whenpatients undergo menopause . It has also beennoted that in many women disease flares aremore common during the second half of themenstrual cycle, after the midcycle surge of oestrogen .




The administration of exogenous estrogens inthe form of OC pills and HRT may exacerbatethe disease in patients with existing lupus .




Chronic hyperprolactinaemia induced bypituitary gland implantation stimulatesprimary humoral antibody responses and

accelerates autoimmune phenomena in lupusprone mice

Recent data suggest that the stimulatoryactions of estrogens on auto reactive B cellsrequire the presence of prolactin .




A dopamine agonist that selectively inhibitsprolactin secretion from the pituitary, hasbeen shown to be useful in the treatment of non-life threatening SLE .




Gonadotrophin releasing hormone (GnRH), aproduced by the hypothalamus, regulates therelease of LH and follicle stimulating hormonefrom the anterior pituitary . Recent animalstudies show that GnRH is immunostimulatory .



PATHOGENESIS OF SLE

To understand further pathogenesis of SLEsome idea about immune system is required .



P HAGOCYTES

The macrophages ("bigeaters") are slower torespond to invaders havefar greater capacities . M acrophages start out aswhite blood cells calledmonocytes . M onocytesthat leave the bloodstream turn intomacrophages inextracellular space .



P rofessional antigen presenting cells

Common A P C areM acrophagesD

endritic cellsP lease note that the B cells also act as antigenpresenting cells .



PATHOGENESIS OF SLE

When antigen crossesthe blood capillary andreaches to extracellular

space .



After crossing of antigen the macrophage or Bcell which are present in extracellular space then

immediately come in contact with antigen .



The antigen is taken inside the macrophagecell and broken into smaller fragments or

peptides called epitopes.



Antigen after being broken into peptides/smaller fragmentscombines with another protein inside the cell called major

MHC-complex , and in this combination is brought to thesurface of cell to be presented to T-helper cell or B cell



PATHOGENESIS OF SLE



PATHOGENESIS OF SLE

Or if antigen-antibody has already formed inblood and once it reaches extracellular spacethe antigen-antibody complex are takentogether inside macrophage or B cell .



PATHOGENESIS OF SLE

Or it can also happenlike this that whenantigen reaches to

extracellular space itunites with antibodyalready present inextracellular space to

form antigen-antibody complex .



PATHOGENESIS OF SLE

Because the B cell has antibody on its surfaceas a receptor that recognizes the antigen .

Once the antigen (or antigen-antibodycomplex) are brought inside the cell, theantigen is broken into smaller fragments theepitopes that combine with M HC-2 and

brought to surface of B cell to be presented toT helper cell .



First, the APC usually amacrophage engulfs

the antigen. Enzymes(peroxides) inside theAPC break down theantigen into smallerparticles



The processed antigens aretransported to the surface of the APC, where it binds withMHC (major histocompatibilitycomplex)



This complex (part of aforeign substance andM HC) is now presented to(CD 4 T-helper cell ) or C D 8(cytotoxic T cell) which the

T-cell receptor (TCR)recognizes and binds to .

The T helper cell role is

only to help and not to kill .



Antigen with M HC-complex2, combines with C D 4 T helper cellotherwise with M HC-1 with C D 8-T helper cell .



The macrophage or B cellalso called as antigenpresenting cell thus in thisway presents smallfragment of antigen toCD4 T helper cell or to CD8T cell (cytotoxic T cell)which the T-cell receptor

(TCR) recognizes and bindsto.

The T helper cell role is

only to help and not to kill,while as C D 8 can kill theantigen and the cell thatpresents it ..



` As soon as APC combineswith T cell , the APC gets

activated and secretesfollowing cytokines.

` Interleukin-1 (IL-1)` Interferon-alpha (IFN-a)`

Interferon-gamma (IFN-g)` Tumor necrosis factor

(TNF)` And other factors that

activate lymphocytes andother immune cells to

respond to the antigens.



Effects of IL-1

On exposure to IL-1, the other inflammatory cellsget affected and stimulated to produce followingfactorsInterleukin-6 (IL-6)P rostaglandin's (e .g , P GE2) , and platelet-activating factor, which are involved in increasedpermeability ,vasodilatation and in the painmechanism .

The mast cells in the vicinity also get activated torelease histamine, heparin for capillary vaso-dilatation .



Effects of IL-1

Cells in vicinity also secrete Chemokines .

So that more and more inflammatory cells areattracted and reach the site of antigen to dealwith .

There also occurs activation of T cells theirproliferation so that more T cells reach at thesite of antigen along with neutrophilis andother inflammatory cells .



Effects of IL-1



Effects of IL-1

Although peripheral T cells are activated,both their capacity for proliferation inresponse to cytokine stimulation productionare reduced in SLE .

Enhances activity of NK cells /cytotoxic T cells .



IL-1 also causes increased production of inducible nitricoxide synthase and consequently high levels of nitricoxide responsible for dilatation of vessels .

Effects of IL-1



IL-1 also activates

endothelial cellsand inducesstimulation of adhesion molecule

expression onendothelial cells.



Firm Adhesion Rolling &Transmigration of neutrophilis & other cells to reach site of

antigen by chemo attractants etc



Effects of IL-1

The end result of these of IL-1 and TNF-ainclude activation and migration of leukocytesand lymphocytes from the blood intoinflammatory tissues .



Tumor necrosis factor

Tumor necrosis factor (TNF, cachexin orcachectin and formally known as tumornecrosis factor-alpha) is a cytokine involved insystemic inflammation .

Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH)



Tumor necrosis factor

Suppressing appetite, induces neutrophilproliferation and increase in C-reactive proteinand induces insulin resistance result in

cachexia, a wasting syndrome by proteincatabolism, lipid depletion and necrosis of cells .

TNF is able to induce apoptotic cell death, toinduce inflammation, and to inhibittumorigenesis and viral replication .



IL-10 in SLE

Also in case of SLE, the Th2 helper cell role is muchmore prominent that secrete IL-10 than Th1 cells .

M eans there is switching of Th1 to Th2 response in SLE .

IL-10 is mainly produced by monocytes, activatedmacrophages, antigen-presenting cells and to a lesserextent by some activated B cells, subsets of C D 4+helper cells like TH1 cells,TH2 cells, mast cells andsome non hematopoietic sources (e .g. , keratinocytes,colon carcinoma, melanoma cells) .



IL-10 & B cells

Now as said that IL-10produced by Th2 cellsetc stimulate

proliferation of B cellsand theirtransformation intoplasma cells .

The plasma cells in turnproduce antibodies .



IL-10 & B cells

Even the B cell will haveantibody as receptor onits surface which the T-helper cell will recognize

when antigen binds tothis B cell surfaceantibody .

The T-helper cell willthen get it inside alongwith antibody as alreadysaid at the site of antigen .



IL-10 & B cells

Antibodies are so enormously formed thatthey take antigens of normal tissue as non-self due to loss of tolerance and make these cellseasily killed and destroyed due to antigen-antibody reaction and inflammation .



IL-10 & B cells

P romotes the development of immunologictolerance .

D ecreases production of inducible nitric oxidesynthetase , a vasodilator .

The cumulative effect of these functions is toinhibit T cell-mediated immune inflammation,

production of B cells and antibodies as well asdecreased antigen presenting capacity .



IL-10 & B cells

Therefore enhances B cell survival,proliferation, and antibody formation .

The gene for IL-10 is in chromosome region1q31-q32



IL-10 & B cells

Also it has been seen that the cells thatnormally suppress B cell activation, such asCD 8+ suppressor T cells and NK cells aredefective in their suppressive activity .

Because there is overall decrease in T cells ascompared to B cells .

Gelatinase B or M atrix M etallo P roteinase



Gelatinase B or M atrix M etallo- P roteinase9 (MMP -9)

This enzyme is one of a group of metalloproteinase's (which includescollagenase and stromelysin) that are involvedin connective tissue breakdown ..

Gelatinase B or M atrix M etallo-



Gelatinase B or M atrix M etallo-P roteinase 9 ( MMP -9)

Normal cells produce MMP -9 in an inactive, orlatent form . The enzyme is activated byinflammatory mediators such as TNF-alphaand interleukin-1

Gelatinase B or M atrix M etallo-



Gelatinase B or M atrix M etallo-P roteinase 9 ( MMP -9)

Breakdown of extracellular collagen andelastin etc pave easy way and help cells tomove easily in extracellular matrix to reachsite of inflammation after migration of cellsfrom vessels .

Elastin & collagen barriers are eaten



Elastin & collagen barriers are eatenaway



ROLE OF ANTIBOD IES

Antibodies are released from the plasma cellso that they can seek out intruders and helpdestroy them . P lasma cells produce antibodies

at an amazing rate and can release tens of thousands of antibodies per second .

So that blood as well as extracellular spaces

are flooded with antibodies .



ROLE OF ANTIBOD IES

The attached antibodies serve as anappetizing coating for eater cells such as themacrophage .

Antibodies also neutralize toxins /antigens andincapacitate viruses, preventing them frominfecting new cells .



C C

antigen

C = constant

V = variable

shape of antigen fitsshape of binding site

antigen-bindingsites

antigen bindsto binding site

lightchain

heavychain



ROLE OF ANTIBOD IES

Each branch of the Y-shaped antibody canbind to a different antigen, so while onebranch binds to an antigen on one cell, the

other branch could bind to another antigen onother cell - in this way pathogens /antigensare gathered into larger groups that are easier

for phagocyte cells to devour.



Role of Complement P roteins

Bacteria and other pathogens /antigenscovered with antibodies are also more likely tobe attacked by the proteins from the

complement system .

The complement system consists of 9 specialproteins (designated C1-C9) that

supplement/help or complement the action of antibodies




C1 binds to antibodythat is bound to antigen(antigen-antibody [Ag-

Ab complex) on thetarget cell surface .




The Ag-Ab complexcatalyzes a series of chemical reactions that

ends with inactive C3converting to its activeform, C3b, which thenbinds to the surface of

the target antigen.

Once bound, C3b



,stimulates phagocytosisand promotesinflammation . C3b alsotriggers reactions thatlead to the creation of amembrane attackcomplex ( M AC) thatcreates pores in themembrane of the target

cell, like holes blown inthe hull of a ship .



O O A OD S



ROLE OF ANTIBOD IES

The antibody has prepared the antigen foreating by the phagocytic cells . The termopsonin is used to describe substances that

enhance phagocytosis .

ROLE OF ANTIBOD IES



ROLE OF ANTIBOD IES

Opsonization can also happen due to coatingof microbes with complement components,such as C3b .

Opsonized particles are more easilyphagocytosed due to the presence of complement receptors on the plasma

membrane of phagocytic cells .

ROLE OF ANTIBOD IES



ROLE OF ANTIBOD IES

IgG is a good opsonin . Binding of IgG to Fcreceptors on other types of cells results in theactivation of other functions .

ROLE OF ANTIBOD IES



Neutralization of toxins /antigen activityImmobilization of microorganismsBinding with soluble antigen , clumping of insoluble antigens (precipitation) , facilitatesthe ingestion of the antigen by phagocyticcells

Activating complement, complementcomponents are also opsonins

ROLE OF ANTIBOD IES



ROLE OF ANTIBOD IES

ACTIVATION OF COMP LIM ENTS-LEAD S TOCELL LYSISThus making also antigen immobile, inactiveharmless and easily digestible by phagocytes.

ROLE OF ANTIBOD IES



ROLE OF ANTIBOD IES

But what happens in SLE the antibodies reactwith normal antigens of normal cells of thebody making them prey for easy lyses by

immune response as said already .

ROLE OF ANTIBOD IES



ROLE OF ANTIBOD IES

Because due to consumption of complimentsthe level of compliments gets reduced evenmay be hereditary deficiency of compliments

in SLE.

A tib di i l d i SLE



Antibodies involved in SLE

So these antibodies act against almost all cellsof the body to their nuclear, cytoplasmic andcell-surface antigens .

To double-stranded D NA, histones andribonuclear antigens in SLE .





The presence of autoantibodies can usually bedetermined by the antinuclear antibody alsoknown as anti-nuclear factor or ANF (ANA)

test performed on patients serum from blood . The titer, or strength, of the ANA gives a roughindication of the severity of the disease .





Not all positive ANA tests indicateautoimmune disease, particularly when thetiter is low . After a positive screening ANA

test, more specific tests for SLE includedetection of auto-antibodies to doublestranded D NA and to Smith antigen .

Antibodies in ol ed in SLE




Antibodies to double stranded D NA (dsD NA)are thought to be of importance in thepathogenesis of SLE . These antibodies are

observed in approximately 60-70% of SLEpatients .





Using serum from military personnel that wasstored before any diagnosis with SLE, Arbuckleet al . found that anti-ds D NA antibodies were

present in the serum years before diagnosis of the actual disease . This suggests that anti-ds D NA antibodies can

be used as a marker for people who may be atrisk for developing SLE .





The Sm proteins were first discovered asantigens targeted by so called Anti-Smantibodies in a patient with a form of systemic

lupus erythematosus (SLE) .

They were named Sm proteins in honor of this

patient, Stephanie Smith .





The Sm antigen is designated as a smallnuclear ribonucleoprotein (snRN P ) and iscomposed of a unique set of uridine rich RNA

molecules bound to protein associated withthe RNA molecules . Anti-Sm antibodies react with snRN P core

proteins .





La protein is involved in RNA metabolism andplays a role in the transcription of RNApolymerase III, was originally defined by its

reactivity with autoantibodies from patientswith Sjogren syndrome .





Anti-Ro/SSA and anti-La/SSB antibodies, whichare directed against two extractable nuclearantigens, have been detected with high

frequency in patients with Sjögren'ssyndrome .





SSA/Ro are different epitopes on solublecellular component nuclear and cytoplasmicpolypeptides associated with small RNAs

called scYRNA situated mostly in thecytoplasmic compartment (70%) and few inthe nuclear compartment (30%) .frequentlyproduced in patients with Sjögren's syndromeand systemic lupus erythematosus .





Ribonucleoprotein (RN P ) is a nucleoproteinthat contains RNA, i .e . it is an association thatcombines ribonucleic acid and protein

together .





Identification of a nuclear protein (Scl-70)recognized as topoisomerase I in 1986 withanti-centromere antibodies as a unique target

of human antinuclear antibodies inscleroderma .

Topoisomerase is an enzyme that relaxes the

strain on D NA by nicking and ligating the D NA.





Following detection of a high titer of ANAs(e .g. 1:160), various subtypes are determined . These include:

Anti-ENA (Extractable nuclear antigen)





A process for preparing nucleoproteic materialwhich comprises immersing organic materialinto a suitable solvent for a sufficient time to

extract nucleoproteins from said material,adding a sufficient amount of an acid to forma precipitate of nucleoproteic material, andrecovering said nucleoproteic materialprecipitate .





Anti-Ro/SSA and anti-La/SSB antibodies, whichare directed against two extractable nuclearantigens, clinically by immunodiffusion, ELISA,

or Western blot .

ANA classification



ANA classification

Anti-Ro (SS-A)Anti-La (SS-B)Anti-Sm (Smith antigen)Anti-nRN P (nuclear ribonucleoproteins)Anti Scl-70 (topoisomerase I)Anti-JoAnti-gp-210 (nuclear pore gp-210)Anti-p62 (Nucleoporin 62)

Anti-ds D NA (double-stranded D NA)Anti-centromere

Helper and Killer T Cells




Now coming again to the point that T cells aswell as B cells are stimulated when A P Cpresents antigen to T helper cells .

In SLE B cell response is overwhelming due toIL-10 especially secreted by Th2 cells .





M ore and more helper T cells circulate in thebody hunting for diseased or infected cellsbearing antigen or pathogen inside their cells .



Cytotoxic T cells



Cytotoxic T cells

Activated killer T cells/(or "turned on") orcytotoxic T cells with C D 8 receptor recognizesantigens kill cells that contain foreign particles

(antigens) by attaching to them and injecting atoxic chemical perforin so that holes form inthese cells that then swells and bursts as wellas antigen getting destroyed .

Cytotoxic T cells/Killer T cells



1 Cytotoxic T cell bindsto infected cell

P erforinmolecule CytotoxicT cell

Holeforming

Infecte cell

Infected cellis destroyed





Suppressor T cells (also called Regulatory T cells)



pp ( g y )

limit responses of other cells (B & T cells)M ake immune response self-limitingP revents excessive immune response whichmight be detrimental to bodyM ay also prevent immune system fromattacking a person's own cells (= tolerance)

D efective Suppressor and M emory T



cells in SLE Suppressor T cells (also called regulatory T

cells) tell the immune system when the fightwith the diseased or infected cells is over, and

the killer T cells are no longer needed .

D efective Suppressor and M emory T



cells in SLE Regulatory T cells are important in preventing

an overactive immune system . There areproblems with the regulatory T cells in SLE

that lead to autoimmune diseases, such asrheumatoid arthritis, multiple sclerosis aswell .

D efective clearance of apoptotic cells



in SLE Autoimmunity possibly results in defective

clearance of apoptotic cells due to theextended exposure of large nuclear and

intracellular autoantigens derived fromenormous number of necrotic cells .

D efective clearance of apoptotic cellsi SLE



in SLE B and T cell tolerance for apoptotic cells is

abrogated, and the lymphocytes get activatedby these autoantigens; inflammation and the

production of autoantibodies by plasma cellsis initiated .

Tingible Body M acrophages (TB M )



Tingible Body acrophages (TB )

A Tingible body macrophage is a type of macrophage -- large phagocytic cellspredominantly found in germinal centers of

lymph nodes, containing many phagocytosed,apoptotic cells in various states of degradation, referred to as tingible bodies(tingible meaning stainable) .




g y p g ( )

Tingible body macrophages normally engulf Bcells and contain condensed (nuclear bits)chromatin fragments .




g y p g ( )

In healthy conditions, apoptotic lymphocytesare removed in germinal centres byspecialized phagocytes, the tingible body

macrophages (TB M ), which is why no freeapoptotic and potential autoantigenicmaterial can be seen .




g y p g ( )

But body macrophages (TB M ) in SLE are fewin number .

even show a definitely different morphology

in SLE; they are smaller or scarce and dieearlier there by engulfing of B cells is reducedB cells form plasma cells then antibodies .




g y p g ( )

The defect in apoptosis is thought due toinherited compliment deficiency likecomplement proteins, such as c1,C2, C4, or

C1q .




g y p g ( )

Also, uningested apoptotic nuclei of cells can befound outside of TB M s.This material may presenta threat and act as antigenic .

D efective apoptosis leading to the prolongedsurvival of pathogenic lymphocytes was thoughtto be one disease mechanism for SLE .which isassociated with defective Fas (C D 95) receptors onthe surface of lymphocytes .

THANK YOU SO MUCH



Trust the physician and the teacher, and drinkhis remedy in silence and tranquility . For hishand though heavy and hard is guided bytender hand of unseen . And the cup he brings,though it burn your lips has been fashioned of the clay which the potter have moistened withhis tears and sacred feelings .

pathogenesis systemic lupus erythematosus by dr bashir ahmed dar associate professor medicine sopore...

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