IMMUNOPATHOLOGY
There are occasions when the immune system is itself a cause of disease or other undesirable consequences . The system can fail in one of three ways.
1) Inappropriate reaction to self antigens ; Autoimmunity .
2) Ineffective immune response ; Immunodeficiency .
3) Overactive immune response ; Hypersensitivity.

AUTOIMMUNITY
Normally the immune system recognises all foreign antigens and reacts against them , while recoganising the body's own tissues as ' self 'and making no reaction against them. If The system should react against self components, autoimmune disease occurs .
Ideally, at least three requirement should be, met before a disorder can be categorised as truly due to autoimmunity,
1. The presence of an autoimmune reaction
2. Clinical or experimental evidence that such a reaction is not secondary to tissue damage but is of primary pathogenetic significance, and
3. The absence of another well defined cause of the disease.
Unfortunately, these requirements are met only in a few diseases, such as SLE, and autoimmune blood dyscrasias.

The autoimmune disorder forming spectrum on one end of which are conditions in which auto antibodies are directed against a single organ or tissue(organ specific).There fore resulting in localised tissue damage. A classic example is Hashimoto's thyroiditis, in which the antibodies have absolute specificity for thyroid constituents. At the other end of the spectrum is SLE, in which a diversity of antibodies results in wide spread lesions through out the body (non organ specific).In SLE auto antibodies react with nuclear constituents of virtually every cell with in the organism. in the middle of the spectrum falls the Goodpasture's Syndrome, in which antibodies to basement membrane of lung & kidney induce lesions and symptoms in these organs. It is obvious that autoimmunity implies loss of self tolerance.

Immunologic Tolerance
Immunology tolerance is a state in which the individual is incapable of developing an immune response to a specific antigen. Self tolerance refers to lack of responsiveness to an individual’s antigens, and obviously it underlies our ability to live in harmony with our own cells and tissues. Several mechanisms, abbeit not well understood, have been postulated to explain the tolerant state.

There of these are important.
1. Clonal deletion:- immature Tcell clones with T cell receptors (TCR) that have high affinity for self antigens are deleted in the thymus during development. A similar negative selection also occurs during Bcell development. How ewer, clonal deletion is not perfect,and normal Bcells can be found with surface Ig against self antigens, (Eg:, DNA, myelin, collagen, and thyroglobulin).
2. Clonal anergy:-this refers to irreversible functional inactivation of developing T&B cells.One mechanism of clonal anergy is recognition of antigen in the absence of co-simulatory signals from the antigen presenting cell.
3. Suppression of auto reactive Leucocyte:-components that actively supress immune responses to self include suppressor T cells and their products,such as TGF-b1 and IL-10.

Mechanisms of Autoimmune Diseases
The pathogenesis of autoimmunity appears to involve immunologic ,genetic and viral factors intracting through the complicated mechanisms that are poorly understood .
Immunologic mechanisms:- Four general mechanisms for loss of self- tolerance have been postulated.

A. bypass of helper T cell tolerance :- tolerance of CD4 + helper T cell is critical to the prevention of autoimmunity. Tolerance to a self antigen is often associated with clonal deletion or anergy of carrier specific helper T cells in the presence of fully competent hapten specific B cells. Therefore ,tolerance may be broken if the need for tolerant helper T cells is bypassed or substituted.

1) Modification of the molecule
if a potentially autoantigenic determined (hapten) is complexed to a new carrier ,the carrier part of the complex may be recognised by non tolerantT cells as foreign. The latter would then cooperate with the hapten- specific Bcells , leading to the production of auto antibodies. This modification of the molecule could arise in several ways.
-complexing of self antigens with drugs or micro organisms
-partial degradation of autoantigens

2) Molecular mimicry
Several infectious agent cross react with human tissue through their haptenic determinants (B cell epitomes). The infecting microorganisms may trigger a antibody response by presenting the cross reacting haptenic determinant in association with their own carrier ,to which the helper T cells are not tolerant. Once the infectious agents provoke tissue damage , their continued presence is not necessary because tissue injury releases more self antigens .

3) Polyclonal lymphocytic activation
Direct (Tcell independent) polyclonal B cell activation by micro organisms and their products e.g. bacterial lipo polysaccharide (endotoxin) or Epstein- Barr virus.
B. Imbalance of supressor-helper T cell function
Loss of supressor T cell has been implicated in the development of auto immunity in several animal models and is suspected in human auto immune diseases. Excessive T cell helper may drive B cells to extremely high levels of auto antibody production

C. Emergence of a sequestered antigen
Any self antigen that is completely sequestered during development is likely to be viewed as foreign if introduced into the circulation and an immune response will develop. Spermatozoa , myelin basic protien, and lens crystallin fall into this category of antigens

HLA linkage (especially to the DR antigens) and familial clustering in some autoimmune diseases suggest a genetic component. Exogenous infection with bacteria , mycoplasmas or especially viruses may also trigger autoimmunity, suggesting an exogenous component as well.

SYSTEMIC LUPUS ERYTHEMATOSIS

Syn: Disseminated lupus erythematosus
Definition :it is an inflammatory disease of autoimmune nature involving the connective tissue of several organ systems and associated with a variable course.

SLE is world wide in distribution. In india it constitutes 1-2% of the major rheumatological problems. Females predominate and the male to female proportion being 1-18. The disease is rare before below the age of 5 years, but children account for 20 %. More than 60% of cases are between the ages of 30-60. SLE results from a gross disturbance of immune mechanisms. Normal body constituents are rendered immunogenic by various damaging factors such as exposure to sunlight infection tissue injury,drugs or others. Among these, viral infection and drugs top the the host’s own tissues. Antinuclear antibodies are mainly seen. ANAs are commonly detected by indirect immunofluorescence. However, ANAs occur in other autoimmune disorders and in up to 10% of normal individuals, but anit-double stranded (native) DNA and anti-smith anitgen antibodies strongly suggest SLE.

ANA can not penetrate intact cells. However, nuclei of damaged cells react with ANA, los their chromatin patterns, and become homogenous LE bodies (hematoxydin bodies). Phagocytosis of LE bodies by neutrophils or maltrophages in vitroforms LE cells in up to 70% of patients with SLE.

In addition to ANAs, lupus patients have many other antoantibodies, some directed against blood elements. (red cells, plate lets, leukocytes) In addition up to 20% to 40% of patients have antiphospholipid antibodies. Some bind to cardiolipin antigen giving rise to false - positive VDRL test. Antiphospholipids antibodies interfere with the formation of prothrombin activator complex in the process of blood coagulation. In vitro tests may reveal prolonagation of the coagulation tests such as APTT, and hence these antiphospholipid antibodies are also knwon as lupus anticoagulant. These so-called lupus anticoagulant actually exert a procoagulant effect in vivo, causing recurrent vascular thromboses, miscarriages, and erebral ischemia. Their mechanism of action in vivo is unknown.

Etiology and pathogenesis
Monozygotic twin concordance (50 to 60%) and familial and HLA clustering suggest a genetic predispositon. HLA types B8 and DR3 and inherited deficency of C1, C4 and C2 complement are known to be associated with a higher incidince of SLE. In addition, exogenous factors such as drug exposure ultraviolet (UV) irradiation, Virus infections and estrognes are also involved.

Although the actiology is unknown, the pathogensis is thought to involve some basic defect in the maintenance of self-tolerance with activation of B cells. This may occur secondary to some combination of
- Heritable defects in the regulation of B cell proliferation.
- Helper T-cell hyper activity.
- Defects in suppressor T cell function.

Morphology
Typical in all tissnes is an acute necrotizing vasulitis with fibrinoid deposits, involving small arteries and arterides. Ig, DNA, and C3 may be found within vessel walls. Skin and muscle one most commonly involved. A perivascular lymphocytic infiltrate is frequently present.
In chronic cases, vessels show a fibrous thickening and duminal narrowing.

Kidney
Involved in virtually all cases of SLE. There are five patterns of lupus nephritis.
a. Class I. Normal by light, E M, and fluorescence mocroscopy. rare.
b. Class II - Mesangial lupus glomerulo nephitis (GN), present in about 25% of patients, associated with minimal hematuria or proteinuria. Slight increase in mesangial matrioc and cells with granular messangial Ig and complement deposits.

c. Class III - Focal proliferative GN; 20% of patients; associated with recurrent hacmaturia, moduate proteinuria, and occasional mild renal in sufficiency. Focal and segmental glomerular swelling with endothelial and mesangial proliferation, neutrophil infiltration and some times fibrinoid deposits and capillary thromble.

d. Class IV - Diffuse proliterative GN : 35% to 40% of patients, many of whom are overtly symptomatic, with microscopic to gross hemature a, proteinuria (some times nephrotic range), hypertension and diminished glomerlar filteration rate. Most glomeruli show endothelial, mesangial and occasionally epithdial profilferation. IC deposits are typically subendothelial, and when extensive form ‘wire loops’. Frequently, there are also tubular changes with granular IC deposits in basement memberances and interstitial changes. Most severe form of lupus nephritis, carrying the worst prognosis.

e. Class V - membranous GN, 15% of patients : induces severe proteinaria or nephrotic syndrome. Diffusely thickened capillary walls similar to idiopathic membranous GN and characterised by subepithelial IC deposits.

SKIN
Classically, malar erythema, including bridge of nose (‘butterfly rash’)
Also, variable cutaneous lesions from erythema to bullac else where. Sunlight exacerbates the lessions. Microscopically, there is basal layer degeneration with dermal - epidermal junction Ig and complement deposits. The dermis shows variable fibrosis, perivasular mononulear cell infilterates, and vasular fibrinoid change.

Joints
Typically a nonspecific, nonerosive synovitis. Minimal joint deformity incontrast to rhenmatoid arthretis.

Central Nervous system (CNS)
Neuropsychiatirc manifestations probably seconday to endothelial injury and occlusion (antiphospholipid antibodies) or impaired neuronal function.

Serositis
Initially fibrinous with focal vasculitis, fibrinoid neerosis, and edema progressing to adhesions, possibly oblitearating serosal cavities (ie pere cardial sac).

Heart : characteristic non bacterial verrcous endocardities (Libman - Sacks endocanditis) much less frequent with the use of steroids. Typically, numerous small, wanty vegetations (0.5 to 4mm) occur on the inflow and or outflow surfactes of the mitral and tricnspid valves. Micro scopically, they are composed of necrotic dibris, degenerating fibro blasts, in flammatory cells and fibrinoid material.

An increasing number of younger patients, especially those treated with corticosteriods, have clinical evidence of cornary artery disease. The pathgensis of the cornary altherosclerosis is not cleaur.

Spleen
Moderate spleenomegaly with capsular thickening and follicular hyperplasia. Marked perivascular fibrosis around penicilliary arteries is characteristic, producing an onion - skin appearance. Ig, c3 and DNA are found with in these vessels.

Lungs
Pleuritis with pleural effusions, interstitial pneumonitis, and diffuse fibrosing alvealitis, all probably related to IC deposition.

Clinical Course
SLE presents insidionsly as a systemic, chronic recurrent, febrile illness with symptoms referable to virtually any tissue, but especially joints, skin, kidneys and serosal membrones.
Auto antibodies to the matologic components may indue thrombocytoperia, leukopenia and anemia. The clinical manifestations are protean.

Clinical manifestations       Prevalence in patients
Hematologic                                 100
Arthritis                                         90
Skin                                              85
Fever                                             83
Fatigue                                          81
Weight loss                                   63
Renal                                            50
Pleurisy                                         46
Myalgia                                         33
Pericaritis                                     25
Crastro intestinal                           21
Raynauds phenomenon                  20
Central nervous system                  20
Occular                                         15
Peripharal neuropathy                     14
Prenumonitis                                   11
Clinical manifestations Prevalmic in pts (%)
Parotid gland enlargement                  8
Liver disease                                     2

The course of the disease is highly variable, rarely it is fulminant with death in weeks to months. Sometimes, the disease may cause minimal symptoms (haematuria, rash) and remit even without treatment. More often, the disease is characterised by recurent flares and remissions over many years and is held in check by immunosuppressive regimens.

Ten - year survival is approximately 70%, death is most commonly caused by renal failure or intercurrent infections pregnancy is associated with risks to mother & father.

Discod lupus (DLE):
A disease limited to certaneous lesions that grossly and microscopically mimic SLE. only 35% of patients have a positive ANA. The lesions show scaling, atrophy, telengiectasia and Keratotic plugging. They heal with considerable scarring.

In contrast to SLE, only lesional skin has deposits of Ig complement in the basal membrance. After many years, 5 to 10% of affected individuals develop systemic manifestations.

Drug - Induced LE
Drugs such as hydralazine, procainamide, isonizid and D-pencillamine frequently induce a positive ANA, less often an LE like syndrome with the latter, although there is multiorgan involvement, renal and CNS disease is an common. Anti double stranded DNA antibodies are rare, but anithistone antiboides are common. There is linkage with HLA - DR4. Drug related LE usually remits after cessation of the offering agent.

Laboratory Investigations
SLE gives rise to an array of abnormalities, some being specific and the other nonspecific. The nonspecific features include, markedly elevated ESR (above 100mm/1st h.), moderate anemia, leukopania, thromboc- ytopenia, and moderate to severe proteinuria. The specific tests depend upon the immunological abnormalities and they are discribed as follwos.

Serolouical abnormalities in SLE
The antinuclear antibodies (ANA) :- They occur in over 95% of cases. These are composed of antibodies against DNA single strand, DNA double strand RNA and several other nuclear components. LE cell phenomenon is due to antinuclear antibodies.

Other immunological markers which are nonspecific are anticytoplasmic antibodies, lymphocytoxins, antibodies against R.B.C, W B.C and platelets, circulating anticoagulants, antithyroid and other organ specific antibodies, rehumatoid factor, flase positive wassermann reaction and VDRL, cryoglobulins, and circulating immune complexes. Levels of complements C3 and C4 are reduced.

Presence of antinuclear antibodies and demonstration of LE cells should make the diagnosis reasonably certain.

Diagnosis
The diagnosis of SLE should be suspected if there are febrile episodes with multisystem involvement and high ESR, not responding to general line of treatment. The American rheumatism Association (ARA) has laid down criteria for diagnosis of SLE. These help to distinguish SLE from the other reheumatic disorders. The important criteria are facial rash, discoid lupus, Ranand’s phenomenon alopecia, Photsensitivity, Oral and rasophaynaged uleeration, artlaitis, neuropsychiatiric manifestions and laboratory features.

Management
Since there are no curative measures, the main aim is to induce remission and prevent relapses. General management consists of avoidance of direct sun light and offending drugs and prompt attention to complications.

References
1. Basic pathology by Kumar, Cotrans, Robbins
2. Boyd’s textbook of pathology
3. Davidson’s Principles and practice of medicine
4. Harrison’s internal medicine