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1.

Systemic autoimmune disease

1. Introduction
The systemic or non organ-specific autoimmune diseases were initially described, characterised and categorised using the features
present in the history obtained from patients who suffered from them, and the findings on clinical examination. The disease definitions
take into account also the clinical course of the conditions, and the findings on detailed laboratory investigation using various kinds of
laboratory tests. Although the diseases have been categorised into certain types, the situation is made complicated by the fact that (as
with most human disease of whatever cause) there is great variation amongst patients because:
Different combinations of the many clinical manifestations of any given condition may be present in different patients
The severity of any given clinical manifestation varies greatly between patients
The severity of any given clinical manifestation can change in the same patient over time
Overlap syndromes may exist between separate conditions, or evolve in a given patient
2. Rheumatoid arthritis
Rheumatoid Arthritis (RA) is characterised by persistent inflammation of the synovium leading to varying degrees of joint destruction.
The disease is associated with HLA-DR4 and HLA-DR1 and occurs more frequently in women. The target autoantigen is unknown,
although type II collagen is a candidate. It is possible that in situations of heavy tissue catabolism (as occurs in RA joints) peptides
might be generated from self-antigens that stimulate the clonal expansion of T cells which have escaped negative selection in the
thymus (i.e. activate T cells in a state of clonal indifference, see section 3).
The disease characteristically starts in the small joints (although spares the distal interphalangeal joints), and then spreads to involve
more proximal joints. The synovial membrane undergoes infiltration by lymphocytes (lymphoid follicles arise) causing villous
hypertrophy. MHC class II molecules are strongly expressed on B cells and synovial lining cells. It is thought that the autoantigen is
presented to T cells at this site and that autoantibody production (against immunoglobulins, histones, DNA, collagen) results in
immune complex formation. These are phagocytosed by macrophages and neutrophils, leading to their activation, formation of
reactive oxygen intermediates and release of lysosomal enzymes and thus tissue damage. Release of IL1 and TNF may activate
chondrocytes and osteoclasts causing further tissue damage.
A high proportion of patients with RA have autoantibodies called rheumatoid factor in their serum. These are autoantibodies directed
against the Fc region of human IgG, and may be of the IgM, IgG or IgA class, although IgM rheumatoid factors are the ones most
frequently present in RA. There are also many extra-articular (i.e. non-joint) manifestations of RA. The American Rheumatism
Association criteria are widely used in the diagnsosis of RA.
3. Systemic lupus erythematosus
Systemic Lupus Erythematosus (SLE) is the classical systemic autoimmune disorder. The prevalence is around 1/700 and the annual
incidence of new cases is about 5/100 000. The peak incidence for females is in late middle age, and is somewhat later for males. In
all age groups except neonates, lupus is more common in females than males. The F:M sex ratio in children is about 2:1, increasing to
6:1 after puberty and peaking at 9:1 in late adulthood. In the over 60 age group the sex ratio declines to 3-4:1. Case control studies
have failed to demonstrate any affect of age at menarche, age at first pregnancy, or parity on the disease incidence.
Aetiological data obtained from epidemiological studies have revealed familial clustering. The incidence of SLE in first degree female
relatives of affected patients has been estimated at 2-15%. Concordance in monozygotic twins is 25-60%, compared with around
10% in dizygotic twins.
Mortality data indicates that neither age at diagnosis nor sex influence survival. The most important predictors of survival are renal and
CNS involvement. Both elevated serum creatinine and persistent proteinuria predict premature death from lupus. Specific
immunological parameters (e.g. autoantibodies, hypocomplementaemia) are not predictive of survival. The most common causes of
death in patients with SLE are active renal and CNS disease, infection, and premature coronary artery disease (related to
glucocorticoid therapy).
Although this is a multisystemic disorder, most patients present with isolated manifestations which may lead to confusion with
disorders such as ITP, primary Raynauds, or rheumatoid arthritis. Skin and joint manifestations are the presenting feature in about
75%. Most patients have constitutional symptoms. Other clinical features include glomerulonephritis, lymphadenopathy, anaemia and
leucopenia, pleurisy, mouth ulcers, and CNS disease. To assist in the diagnosis of SLE the American Rheumatism Association has
define a list of 11 criteria and if a patient has 4 more of these over a period of time, may have Lupus.

To see some more details of SLE including clinical and pathology images click here.
4. Scleroderma
Classification
I. Limited (CREST syndrome)
Long-standing Raynauds
Skin changes limited to hands, face, feet and forearms
Skin calcification and telangiectasia
GIT involvement
Late pulmonary hypertension
Dilated nailfold capillary loops without drop-out.
II. Diffuse (Systemic sclerosis)
Truncal and acral involvement
Skin changes within one year of Raynauds onset
Tendon friction rubs
Early interstitial lung disease
Diffuse GIT involvement
Nailfold capillary dilation and drop-out.
Pathogenesis
Scleroderma is a state of dysregulated connective tissue deposition. It is characterised by expansion of dysregulated fibroblast clones
which behave autonomously and overexpress genes encoding elements of the extracellular matrix, particularly type I collagen. There is
also evidence of an underlying autoimmunity: MHC associations, autoimmune serology, familial association with other autoimmune
diseases, predominant inflammatory perivascular infiltrate with activated T cells in regions of fibrosis, and the resemblance to graft
versus host disease. Fibroblasts can be activated by a number of T cell derived cytokines and this may provide one link between
immune activation and the pathology of scleroderma.
Systemic sclerosis is a profoundly debilitating condition, due to the effects on the skin and gastrointestinal tract. As well as causing
significant morbidity, it also has a high mortality (~40% over 5 years), due to pulmonary fibrosis, and renal involvement. CREST
syndrome (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia) is characterised by limited
cutaneous involvement, although severe Raynauds and calcinosis can still lead to severe functional limitations. Renal involvement does
not usually occur in the limited form , but respiratory involvement in the form of pulmonary hypertension may be a significant problem.
60-70% of patients with CREST have anti-centromere antibodies.
5. Sjgren's Syndrome
Sjogrens syndrome (SS) is a relatively common autoimmune disorder characterised by exocrinopathy resulting in the cardinal
manifestations of keratoconjunctivitis sicca (90%) and xerostomia (80%). When these manifestations occur in the absence of another
clearly defined connective tissue disease, the diagnosis is primary Sjogren's syndrome. Secondary SS may occur in association with a
variety of other autoimmune diseases. However, primary SS is best not thought of as simply a diagnosis of exclusion as there appears
to be a discrete pattern of extraglandular involvement which may accompany the sicca complex.
Women are disproportionately affected (90%), and the mean age of presentation is around 52 years. HLA B8, DR3, DR2 and
DRw52 are over-represented in patients with SS.
Glandular Manifestations
1. Keratoconjunctivitis sicca - Diminished tear production is due to destruction of the active secretory apparatus. The tears are
quantitatively and qualitatively altered, with increased osmolarity, diminished IgA, lysozyme and lactoferrin content. Patients may
report dry eyes, grittiness, burning, photophobia, or reduced visual acuity.
2. Xerostomia - Diminished saliva production may manifest as a dry mouth, odynophagia, halitosis, excessive oral pathology and
infections, and dysgeusia.
Extraglandular manifestations of Sjgrens Syndrome.
1. Respiratory disease - Dryness of the upper and lower respiratory tract may lead to inspissated secretions, chronic cough and
recurrent infection. Interstitial infiltrates also occur. In addition, serositis with pleural effusions may predominate.

2. Renal Disease - Interstitial nephritis and tubular dysfunction, most commonly manifesting as renal tubular acidosis, but may progress
to complete Fanconi's syndrome.
3. Neurological - Peripheral and cranial neuropathy have been associated with SS. In addition, CNS involvement has been described
in a small minority of patients in which multifocal lesions occur throughout the white matter resembling MS both clinically and
radiologically.
4. Arthritis
5. Raynaud's phenomenon
6. Cutaneous vasculitis
7. Non-Hodgkin's lymphoma - occurs with increased frequency, often in the mucosa-associated lymphoid tissue.
6. The antiphospholipid syndrome
Antiphospholipid antibodies occur in patients with lupus, but also in patients who do not fulfill the diagnostic criteria for lupus. In both
cases they are associated with several well-defined clinical manifestations:
1. Thromboses in about 40%. Distinguished from other prothrombotic disorders by the presence of both arterial and venous
thromboses (other thrombotic syndromes usually involve either arterial or venous circulations). Emboli from thrombi on heart valves
may also occur.
2. Foetal loss - about 40%. APLAS accounts for about 4% of cases of recurrent foetal deaths
3. Thrombocytopenia - 30-40%
4. Coomb's test positive haemolytic anaemia
Other associations which are less clearly established include chorea, cardiac valvular disease and myocardial infarction.
7. Non Autoantibody tests in systemic autoimmune disease.
The co-ordinated and stereotypical early response to tissue damage or infection mediated by the innate immune system is described
as the acute phase response (APR). The APR is initiated by cytokines and other secretory products of macrophages and/or blood
monocytes, which are activated during acute inflammation. The acute phase response is an altered pattern of protein synthesis by the
liver, which represents a vestigial innate immune response. The are a large number of proteins that are secreted during an APR, but
the most dramatic response occurs with C-reactive protein (CRP). Thus, measuring CRP is often used as an indicator of tissue
damage or inflammation. Another common indicator of the APR is the erythrocyte sedimentation rate (ESR), which is influenced by a
number of different acute phase reactants.
An unusual feature of SLE is that despite causing generalised inflammation and often tissue damage, the autoimmune process fails to
stimulate a normal APR and CRP is not increased. However, intercurrent infections can stimulate a relatively normal CRP response,
which provides a useful way of distinguishing disease activity from infection. In contrast to SLE, the inflammation of RA stimulates a
significant CRP response. Other non-specific markers of inflammation include polyclonal hypergammaglobulinaemia (especially in
Sjogren's syndrome) and thrombocytosis.
Complement components C3 and C4 are also acute phase reactants. However, they may be low in states of complement
consumption, as occurs with active SLE. Interpretation of complement studies in patients with SLE is even more complicated because
inherited complement deficiencies predispose to SLE. For example, a low C4 may reflect consumption, or a deficiency of one or
more of the four C4 alleles.
8. Autoantibodies in systemic autoimmunity

1. Overview of Nuclear Antigens

a. The Structure of the Human Cell Nucleus- The nuclear membrane is a bilaminar structure with pores to allow molecules to
move between the cytoplasm and the nucleus. The outer nuclear membrane is continuous with the endoplasmic reticulum (ER).
The inner membrane contains lamin molecules, which provide sites of attachment for chromatin. Of the nuclear contents, the
major autoantibody targets are chromatin, nucleoli and ribonucleoproteins (RNPs).

b. Chromatin- Chromatin consists of DNA and histone proteins. 146 base pairs (bp) of DNA are wound in almost two turns
around 8 histone molecules to form nucleosomes. Nucleosomes are connected by strands of 60 bp (linker DNA) which
associate with H1 histones. Chromatin is usually insoluble in physiological buffers (c.f. RNP which is soluble; both are labile).
c. Nucleoli -The nucleoli are the largest and most complex RNP structures. They are the sites of assembly of subunits of
ribosomes. Nucleoli disappear at the time of cell division, then reform at the nucleolar organising regions (NORs) which occur
at the tips of the short arms of chromosomes 13, 14, 15, 21 and 22. The genes for ribosomal RNA are found at these sites.
The enzyme RNA Polymerase I occurs only in the nucleolus and is responsible for the transcription of ribosomal RNA.
d. Ribonuclear proteins - The so-called extractable nuclear antigens (ENAs) are mostly small nuclear and small cytoplasmic
RNPs involved in processing RNA. nRNP and Sm antigens are U series RNPs, which are components of the spliceosome and
are involved in the removal of the introns from heterogenous nuclear RNA. The SS-B antigen is a 48 kD protein which acts as
a termination factor for RNA Polymerase III.
2. Antinuclear Antibodies
Patients with SLE usually have multiple autoantibodies, but those which are most specific for SLE are directed at dsDNA and
Sm. Antibodies to histones also occur in SLE. Antibodies to all classes of histones have been demonstrated in SLE and have
also been demonstrated in other disorders. (Antibodies to histone are responsible for the LE cell phenomenon, now only of
historical interest). Antibodies to histones are common in drug-induced lupus. See some images of staining patterns here.
Clinical Relevance of ANA
There are certain limitations in using ANA as a screening test.
i. 20% of healthy relatives of patients with systemic autoimmune disease may have positive ANAs.
ii. 75% of elderly patients who are healthy and 2% of healthy non-elderly individuals may have a positive ANA.
iii. ANA alone is a weak test for: Sjogren's syndrome, scleroderma and polymyositis
Anti-dsDNA Antibodies
About 65% of SLE patients with active disease have anti-dsDNA antibodies but less than 5% have elevated levels when
disease is quiescent. More than 80% of patients with lupus nephritis have elevated levels. Anti-dsDNA antibodies are directed
towards the sugar-phosphate backbone of the DNA molecule, and when present in high concentration (e.g. > 50 IU/ml) make
a diagnosis of SLE very likely. Antibodies to single-stranded DNA are directed towards the nucleotide bases in DNA and are
found in many conditions including SLE, RA, other inflammatory diseases, chronic infections and malignancies. Anti-dsDNA
antibodies play a role in the pathogenesis of SLE but a similar role for the other autoantibodies in SLE or other diseases has not
yet been well established.
3. Anti-Histone Antibodies
Associated with SLE, drug-induced SLE and in a minority of other connective tissue disorders.
Antigens recognised in Drug-induced lupus
H2A, H2B Drug-induced lupus, Procainamide, Hydralazine, methyldopa, penicillamine, quinidine, INH.
H2A, H2B-DNA complex Quinidine, Procainamide (more specific but not for hydralazine, however, idiopathic lupus serum
will also be positive).
___________________________________________________________________________
*IgM anti-histone antibodies occur in patients on drugs associated with lupus but who are asymptomatic. IgG antibodies occur
in those who are symptomatic.
Extractable Nuclear Antigens (ENAs)
ENAs are a diverse cluster of antigens grouped together because they can be extracted from nuclei and solubilised in saline.
They include SS-A, SS-B, RNP, Sm, Jo-1, and Scl-70. The presence of antibodies to ENAs is suggested by speckled
immunofluorescence on the ANA. These proteins are intimately associated with various RNA molecules and are thus called
ribonucleoproteins, but the nomenclature used for them is often a source of confusion. Sm, Ro and La were named after the
first two letters of the surnames of the patients in whom they were first found. Two proteins associated with Sjogren's
Syndrome were independently described as antigens A and B, but are now known to be identical to Ro and La respectively
(i.e. SS-A = Ro and SS-B = La)
AutoAb

Structure

Location

Function

Sm

Protein component of U1,2,4-6 snRNPs

Nuc (N)

Spliceosome components

RNP

Protein component of U1-RNP

Spliceosome component

Ro

60+52kD proteins complexed to cYtoplasmic

RNA molecules Y1-Y5

N+ C

??DNA/RNA melting, RNA transport

or DNA-protein interaction

La

47kD protein, complexed as for Ro proteins

N+C

As above

Jo-1

Histidyl-tRNA synthase

Cyto (C)

Peptide synthesis

Scl70

70kD fragment of DNA topoisomerase I

DNA uncoiling

Centromere

Proteins at inner + outer kinetochore plate

Attachment to spindle

4. Antibodies to RNA-Associated Proteins

There are two pairs of closely associated autoantibodies which occur in systemic autoimmunity:
RNP+Sm
SS-A+SS-B
*Sm almost always occurs with nRNP, but nRNP antibodies may occur alone.
*SS-A always occurs in people with SS-B, but may occur alone.
i. Sm and nRNP Antibodies
RNP and Sm are small nuclear ribonuclear proteins (snurps) that form part of the spliceosome, involved in the removal of
introns from mRNA. Sm is specific for SLE (but only occurs in 20-30% of patients) and when present is predictive of renal
disease (RNP alone predicts against renal disease).
ii. SS-A and SS-B Antibodies.
SS-A (also called Ro) and SS-B (also called La) are found in both nucleus and cytoplasm. Their precise location varies with
the stage of the cell cycle. SS-A antibodies react with at least four proteins of mw 60, 60, 54 and 52 kDa complexed with 4-5
small RNA particles called hY RNAs (hY stands for human cytoplasm; hY1, hY3, hY4, hY5). As with the antigens for Sm
and nRNP, the antigens reside on the protein moieties, not on the RNA although the RNA may be necessary to maintain the
conformation of the epitope. SS-B reacts with a 48 kDa protein complexed with nascent RNA polymerase III transcripts. This
protein (48kD) is a transcription termination factor for RNA polymerase III and is primarily located in the nucleus. This protein
may have a role in the nucleocytplasmic transport of RNA. There is some evidence that this protein can associate with hY5
RNA leading to the association between SS-A and SS-B.
Clinical associations of SS-A include subacute cutaneous lupus, C2 and C4 deficiency, photosensitivity, neonatal lupus,
rheumatoid factor-positive lupus, renal involvement in patients with SLE and pneumonitis.
SS-B is highly specific for Sjogrens syndrome.
Summary of some relatively specific autoantibodies
AutoAb

Specific for

AutoAb

Seen most often in

Sm

SLE

(U1) RNP

SLE, MCTD

Jo-1

Dermato-/poly-myositis

SSA/Ro

Sjogren's (60%), SLE (35%)

Centromere

CREST syndrome

SSB/La

Sjogren's (40%), SLE (15%)

5. Autoantibodies of Inflammatory Muscle Disease

Inflammatory autoimmune muscle diseases include polymyositis (PM), dermatomyositis (DM) and inclusion body myositis
(IBM). 90% of patients with myositis have at least one autoantibody. Most of these recognise cytoplasmic antigens so they are
often ANA negative.
i. Antibodies to Cytoplasmic Antigens, aminoacyl-tRNA synthases

Jo-1 is the best known autoantibody in PM (rare in DM) and is targeted at histidyl tRNA synthase. Jo-1 antibodies occur in
about 25% of PM patients and are associated with pulmonary fibrosis and Raynaud's phenomenon. Jo-1 antibodies tend do
disappear when the disease goes into remission so are useful in monitoring disease activity.
6. Autoantibodies in Scleroderma
About 95% of scleroderma patients have circulating autoantibodies and around 90% have positive ANAs.
i. Anti Centromere Antibodies
Anti centromere are directed to metaphase chromatin, specifically, the kinetochore and are associated with CREST syndrome
(present in about 90% of cases), primary Raynaud's (10-20%), primary biliary cirrhosis.
ii. Scl-70 Antibodies
Antibodies to Scl-70 react with DNA topoisomerase I, which is involved in the relaxation of supercoiled DNA during
transcription. The antibodies to Scl-70 in scleroderma are able to inhibit the supercoiling of DNA. Scl-70 antibodies are almost
exclusive to scleroderma, but also in a small minority of patients with primary Raynauds disease and are predictive of more
extensive disease. Scl-70 antibodies are detected in about 25% of patients with scleroderma, and are more common in
Negroes than Caucasians. Scl-70 antibodies correlate with a more severe clinical course with more extensive visceral disease
and proximal skin tightening. In females, Scl-70 confers an increased risk of malignancy.
7. Antiphospholipid antibodies

Two types of phospholipid antibody may be detected

i. Cardiolipin antibodies
Autoantibodies directed against a complex of a cardiolipin, a phospholipid, and b 2-glycoprotein 1 (a serum glycoprotein which binds
to phospholipids).
ii. Lupus Anticoagulant
The lupus anticoagulant (LA) is directed against the phospholipid portion of the prothrombin activator complex. The LA has been
defined as an antibody that interferes with phospholipid-dependent coagulation tests without inhibiting the activity of specific clotting
factors. The antigen here is probably thromboplastin, which contains several phospholipids but not cardiolipin.
The criteria for the recognition of a LA are:
1. Abnormality of a phospholipid -dependent clotting test, e.g. APTT.
2. The abnormality must be due to an inhibitor of clotting, not a clotting factor inhibitor etc. Thus, mixing studies must be performed.
3. The inhibitor must be directed at PL. Thus, the abnormality should be corrected by the addition of phospholipid or activated
platelets.
It should be remembered that 70% of patients who have these antibodies are asymptomatic.
9. Vasculitis
Vasculitis is inflammation of blood vessel walls, which can result in impairment of function of the tissues supplied with blood by the
blood vessels concerned, and even infarction of the tissues subtended. For reasons that are still not entirely clear, different vasculitides
have a predilection for different combinations of organs - it is possible that this may be due to the restricted or differential expression
in the endothelia of these organs of molecules essential for the immunopathological process to occur. There are many causes and
types of vasculitis. One way to consider them is in terms of the size of the vessel affected.
Classification
I. Large Vessel Vasculitis
Takayasu arteritis
Giant Cell arteritis
II. Medium sized Vessel Arteritis

Classic polyarteritis nodosa

Kawasaki disease
III. Small Vessel Vasculitis
ANCA-associated Wegener's granulomatosis
Microscopic polyarteritis
Churg-Strauss syndrome
Primary pauci-immune necrotising and crescentic glomerulonephritis
Drug-induced (hydralazine, propylthiouracil)
Anti-GBM disease
Mixed cryoglobulinaemia (hepatitis C)
Henoch-Schonlein purpura
Primary cutaneous leucocytoclastic vasculitis
Thromboangiitis obliterans
SLE
Rheumatoid arthritis
10. ANCA-Associated Vasculitis
The approach to vasculitis has been radically changed by the identification of anti-neutrophil cytoplasmic antibodies (ANCA) which
are helpful in the diagnosis of vasculitis. Most importantly, ANCA occurs with Wegener's granulomatosis, Churg-Strauss vasculitis
and microscopic polyarteritis nodosa (mPAN). ANCA may play an important part in initiating disease, although cellular immune
mechanisms probably play a critical and determining role subsequently. There are two principal patterns of ANCA, termed
cytoplasmic ANCA, where the target antigen is Proteinase 3,and perinuclear ANCA, where the antigen is Myeloperoxidase. Most
patient's (90%) with Wegener's granulomatosis have a positive cANCA and about 50% of patients with mPAN are also positive.
However, cANCA and pANCA can be seen in a variety of other disorders including infections, chronic liver and inflammmatory
bowel disease. CRP and ANCA levels can be used to monitor disease activity.
11. Glomerulonephritis
The term glomerulonephritis is applied to immunologically-triggered inflammation which is largely confined to the glomerular tuft. The
high glomerular filtration pressure and the process of ultrafiltration increase the kidneys' susceptibility to potentially toxic substances in
the circulation. There are several basic mechanisms of GN
1. Circulating immune complexes (of whatever origin/cause) tend to be deposited at the glomerulus. Complement activation frequently
follows, with ensuing infiltration by cells, and further inflammation. There are many causes of glomerulonephritis, which has been
classified histologically. However, there is no simple relationship between the histological appearances and the clinical features. A
large variety of infections are associated with glomerulonephritis because immune complexes are deposited in the kidney. The pattern
of damage is at least partly determined by the isotype of the immunglobulin deposited, IgA complexes being less damaging than IgG.
Some of the clinical syndromes and useful investigations are outline below.
2. Autoantibodies targeted to glomerular antigens Goodpasture's disease is due to the presence of anti-glomerular basement
membrane antibodies directed against type IV collagen which bind to glomerular and pulmonary basement membranes causing
glomerulonephritis and haemoptysis. It is rare but rapidly progressive, the prognosis being directly related to the degree of renal failure
at presentation. Without treatment 75-90% of patients die. It may be diagnosed by looking for anti-GBM autoantibodies in serum and
on renal biopsy.
3. Systemic vasculitis- frequently involves the glomerular tuft, e.g. Wegener's granulomatosis, mPAN.
12. Clinical Manifestations of Glomerulonephritis
The glomeruli have a limited number of ways of responding to immunological insults, which give rise to a number of clinical
syndromes.
1. Acute nephritis- haematuria, proteinuria, hypertension and oliguria (Exclude obstruction)
2. Nephrotic syndrome- hypoalbuminaemia, oedema and proteinuria (>3.5g/day)
3. Proteinuria- >300mg/day but without nephrotic syndrome
4. Haematuria- (exclude lesion in upper/lower urinary tract)
5. Renal Failure- acute or chronic Often caused by glomerulonephritis

13. Cryoglobulinaemia
Cryoglobulinaemia is the presence in serum of immunoglobulins which precipitate on cooling, and this may occur as a primary
disorder or secondary to another disease. The clinical features are caused by the obstruction of small blood vessels and the ischaemia
and possible infarction of the tissues which they subtend. They are classified into 3 types:
Type I (25%) are monoclonal (usually IgM) associated with lymphoproliferative disease
Type II (25%) are mixed (monoclonal + polyclonal) with rheumatoid factor activity and associated with
lymphoproliferation and hepatitis C
Type III (50%) are polyclonal and associated with various non-organ-specific autoimmune diseases and hepatitis C.
Clinical syndrome

Pathogenesis

Useful investigations

Post streptococcal GN (Acute

nephritis)

Immune complexes containing streptococcal

Ags get deposited in the kidney. Typically
diffuse proliferative with infiltration by
polymorphs. Good prognosis in kids.

Low serum C3, raised ASO titre. Biopsy shows

lumps of IgG and C3

Membranous Nephropathy
(proteinuria, haematuria or nephrotic
syndrome)

Chronic deposition of immune complexes.

Association with HLA DR3. can occur with
some drugs, chronic infections

Renal biopsy shows thickening GBM with granular

deposits of IgG and C3(also IgA and IgM) C3
normal

Membrano proliferative GN (MPGN)

(acute nephritis, nephrotic syndrome)
type II associated with partial
lipodystrophy

2 types: type II is associated with antibodies

to the C3 convertase, stabilising the complex
and leading to C3 consumption with normal
C4

Renal biopsy in type I disease shows Igs and C3. In

type II, C3 alone is deposited. C3 is low in type II.
Can be low or normal in type I disease

All patterns in SLE

diffuse proliferative GN, membranous GN,

MPGN

ANA, ds DNA, C3, C4. Renal biopsy shows

variable pattern with deposition of IgG and C3

Goodpasture's syndrome (acute

nephritis, acute renal failure,
haematuria, pulmonary haemorrhage)

Typically male smoker's. Can be post

infectious. Abs against glomerular basement
membrane DR2 associated

Anti-GBM abs in serum. Linear staining of IgG on

GBM

ANCA associated GN (acute nephritis,

renal failure, haematuria)

cANCA (Proteinase 3) particularly associated with

Wegener's Granulomatosis pANCA
(Myeloperoxidase) often associated with
microscopic Polyarteritis. Renal biopsy shows
necrosis of often with crescentic GN. Not much in
the way of Igs and Complement

IgA Nephropathy (haematuria,

typically after respiratory infection.
can present as acute nephritis or
nephrotic syndrome)

IgA immune complexes deposited in the

Mesangium HLA-DR4 associated

Renal biopsy shows IgA, C3

Henoch Schonlein Purpura. Purpuric

rash typically over extensor surfaces
associated with infection

IgA immune complexes give rise to skin and

renal lesions

Renal Biopsy shows IgA and C3 as in IgA

nephropathy

Minimal change nephritis (nephrotic

syndrome)

Pathogenesis unknown. Responds to

steroids often. Proteinuria is selective
(albumin)

renal biopsy no Igs or complement

Amyloidosis (nephrotic syndrome,

renal failure

associated with light chain disease in

myeloma, Also primary amyloidosis

Characteristic birefringent staining with congo red

Diseases associated with Glomerulonephritis

Type

Antigen

Disease

Virus

Hepatitis B

Polyarteritis nodosa

Hepatitis C

Mixed essential cryoglobulinaemia

Cytomegalovirus

Glomerulonephritis

Streptococcal

Acute PS GN

Streptococcal viridans

Endocarditis

Staphylococci Albus

Shunt Nephritis

Mycobacterium leprae

Lepromatous leprosy

Bacteria

Parasites

Drugs

Autoantigens

Tumour Ag

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Plasmodium Malariae

Malaria

Schistosoma

GN

Toxoplasmosis

GN

Penicillamine

Drug nephritis

Gold

Drug nephritis

Foreign proteins

Serum sickness

DNA, nuclear Ag

SLE

IgG

Cryoglobulinaemia
Neoplasia