Transcript Autoimmune diseases

Autoimmune diseases
Overview
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Immune reactions against self antigens—
autoimmunity—are an important cause of certain
diseases in humans, estimated to affect at least 1%
to 2% individuals
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the mere presence of autoantibodies does not
indicate an autoimmune disease exists
Pathologic autoimmunity
Three requirements
(1) the presence of an immune reaction specific for some self antigen or self tissue;
(2) evidence that such a reaction is not secondary to tissue damage but is
of primary pathogenic significance;
(3) the absence of another well-defined cause of the disease.
Autoimmune diseases
Clinical manifestations
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Organ disease
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example: diabetes mellitus
Generalised disease
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example: lupus erythematous
Tolerance
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Immunologic tolerance is the phenomenon of
unresponsiveness to an antigen induced by
exposure of lymphocytes to that antigen.
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Lymphocytes with receptors capable of recognizing
self antigens are generated constantly, and these
cells have to be eliminated or inactivated as soon
as they recognize self antigens, to prevent them
from causing harm
Mechanisms of tolerance
Central tolerance
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immature self-reactive T and B lymphocyte clones that recognize self antigens during
their maturation in the central (or generative) lymphoid organs (the thymus for T cells and
the bone marrow for B cells) are killed or rendered harmless
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Negative selection of self-reactive T cells in thymus: When immature lymphocytes
encounter the antigens in the thymus, many of the cells die by apoptosis
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A wide variety of autologous protein antigens, including antigens thought to be
restricted to peripheral tissues, are processed and presented by thymic antigenpresenting cells in association with self MHC molecules and can, therefore, be
recognized by potentially self-reactive T cells
Receptor editing of developing B in bone marrow: B cells that recognize self antigens
in the bone marrow reactivate the machinery of antigen receptor gene rearrangement and
begin to express new antigen receptors, not specific for self antigens.
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If receptor editing does not occur, the self-reactive cells undergo apoptosis, thus
purging potentially dangerous lymphocytes from the mature pool.
Mechanisms of central
tolerance: AIRE
Mechanisms of
peripheral tolerance
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Anergy.
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activation of antigen-specific T cells requires two signals: recognition of peptide antigen in association with self
MHC molecules on the surface of APCs and a set of costimulatory signals (“second signals”) from APCs such as
CD28 on T cells that bind to their ligands (the costimulators B7-1 and B7-2) on APCs.
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If the antigen is presented to T cells without adequate levels of costimulators, the cells become anergic. Because
costimulatory molecules are not expressed or are weakly expressed on resting dendritic cells in normal tissues,
the encounter between autoreactive T cells and their specific self antigens displayed by these dendritic cells may
lead to anergy.
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Several mechanisms of T-cell anergy have been demonstrated in various experimental systems. One of these,
which has clinical implications, is that T cells that recognize self antigens receive an inhibitory signal from
receptors that are structurally homologous to CD28 but serve the opposite functions. Two of these inhibitory
receptors are CTLA-4, which (like CD28) binds to B7 molecules, and PD-1, which binds to two ligands that are
expressed on a wide variety of cells.
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mice in which the gene encoding CTLA-4 or PD-1 is knocked out develop autoimmune diseases. Furthermore,
polymorphisms in the CTLA4 gene are associated with some autoimmune endocrine diseases in humans.
Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter self antigen in
peripheral tissues, especially in the absence of specific helper T cells, the B cells become unable to respond to
subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death.
Mechanisms of
peripheral tolerance
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Suppression by regulatory T cells
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A population of T cells called regulatory T cells functions to prevent immune reactions against self antigens.
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Regulatory T cells develop mainly in the thymus, as a result of recognition of self antigens
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The best-defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2
receptor, and a transcription factor of the forkhead family, called FOXP3.
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Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T
cells. Mutations in FOXP3 result in severe autoimmunity in humans and mice; in humans these mutations
are the cause of a systemic autoimmune disease called IPEX (an acronym for immune dysregulation,
polyendocrinopathy, enteropathy, X-linked). In mice knockout of the gene encoding IL-2 or the IL-2 receptor
α or β chain also results in severe multi-organ autoimmunity, because IL-2 is essential for the maintenance
of regulatory T cells.
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The mechanisms by which regulatory T cells suppress immune responses are not fully defined, but their
inhibitory activity may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10
and TGF-β, which inhibit lymphocyte activation and effector functions.
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Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to
activate T cells via CD28.
Mechanisms of
peripheral tolerance
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Deletion by apoptosis.
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if T cells recognize self antigens, they may express a pro-apoptotic member of the
Bcl family, called Bim, without antiapoptotic members of the family like Bcl-2 and
Bcl-x (whose induction requires the full set of signals for lymphocyte activation).
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A second mechanism of activation-induced death of CD4+ T cells and B cells
involves the Fas-Fas ligand system. if self antigens engage antigen receptors of
self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the
cells via Fas-mediated apoptosis. Self-reactive B cells may also be deleted by FasL
on T cells engaging Fas on the B cells.
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The importance of this mechanism in the peripheral deletion of autoreactive
lymphocytes is highlighted by two mice that are natural mutants of Fas or FasL.
These mice develop an autoimmune disease somewhat resembling human SLE,
associated with generalized lymphoproliferation. In humans a similar disease is
caused by mutations in the FAS gene; it is called the autoimmune
lymphoproliferative syndrome (ALPS).
Immune-privileged sites
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Some antigens are hidden (sequestered) from the immune
system, because the tissues in which these antigens are
located (eye, testis, brain) do not communicate with the
blood and lymph.
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As a result, self antigens in these tissues fail to elicit
immune responses and are essentially ignored by the
immune system.
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If the antigens of these tissues are released, for example, as
a consequence of trauma or infection, the result may be an
immune response that leads to prolonged tissue
inflammation and injury. This is the postulated mechanism
for post-traumatic orchitis and uveitis.
Mechanisms of
autoimmunity
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Autoimmunity arises from a combination of
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the inheritance of susceptibility genes
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environmental triggers, such as infections and
tissue damage
Mechanisms of autoimmunity
Defective tolerance or regulation.
• Despite the advances in understanding mechanisms
of immune tolerance and regulation, it is not known
why these may become defective in the majority of
common autoimmune diseases.
Abnormal display of self antigens.
• Abnormalities may include increased expression and
persistence of self antigens that are normally cleared,
or structural changes in these antigens resulting from
enzymatic modifications or from cellular stress or
injury
Inflammation or an initial innate immune response.
• Microbes or cell injury may elicit local inflammatory
reactions resembling innate immune responses, and
these may be critical inducers of the autoimmune
disease.
Susceptibility genes
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Autoimmunity has a genetic component.
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The incidence of many autoimmune diseases is greater in twins of affected individuals
than in the general population, and greater in monozygotic than in dizygotic twins, proof
that genetics contributes to the development of these disorders.
Greatest contribution: HLA genes
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Example: HLA-B27 and ankylosing spondylitis and HLA-B27; individuals who inherit this
class I HLA allele have a 100-200 fold greater chance (odds ratio, or relative risk) of
developing the disease compared with those who do not carry HLA-B27
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Note that the majority of individuals with this allele will not develop the disease
anyway
Not clear why: not necessarily due to a better ability of some HLA molecules to display
self-antigens
Non-HLA genes and autoimmune diseases
Example: PTPN22. Gene polymorphisms associated with autoimmune diseases reduces the enzymatic
activity of the protein (a phosphatase the limits lymphocyte activation, thus leading to enhanced activation of
lymphocytes in several diseases)
Role of infections
Role of infections
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infections may upregulate the expression of costimulators on APCs. If
these cells are presenting self antigens, the result may be a breakdown of
anergy and activation of T cells specific for the self antigens.
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some microbes may express antigens that have the same amino acid
sequences as self antigens. Immune responses against the microbial
antigens may result in the activation of self-reactive lymphocytes. This
phenomenon is called molecular mimicry.
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A clear example of such mimicry is rheumatic heart disease, in which
antibodies against streptococcal proteins cross-react with myocardial
proteins and cause myocarditis.
Some viruses, such as Epstein-Barr virus (EBV) and HIV, cause polyclonal
B-cell activation, which may result in production of autoantibodies.
General features of
autoimmune diseases
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Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the
damage is often progressive.
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When the response is inappropriately directed against self tissues, physiological
amplification mechanisms exacerbate and prolong the injury. Another reason for the
persistence and progression of autoimmune disease is the phenomenon of epitope
spreading, in which an immune response against one self antigen causes tissue damage,
releasing other antigens, and resulting in the activation of lymphocytes by these newly
encountered epitopes
The clinical and pathologic manifestations of an autoimmune disease are determined by the
nature of the underlying immune response. Some of these diseases are caused by
autoantibodies, whose formation may be associated with dysregulated germinal center
reactions. Most chronic inflammatory diseases are caused by abnormal and excessive TH1
and TH17 responses; examples of these diseases include psoriasis, multiple sclerosis, and
some types of inflammatory bowel disease. CD8+ CTLs contribute to killing of cells, such as
islet β cells in type 1 diabetes. In some autoimmune diseases, such as rheumatoid arthritis,
both antibodies and T cell–mediated inflammation may be involved.
SLE (systemic lupus
erythematosus)
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SLE is an autoimmune disease involving multiple organs, characterized by
a vast array of autoantibodies, particularly antinuclear antibodies (ANAs)
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injury is caused mainly by deposition of immune complexes and binding of
antibodies to various cells and tissues.
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The disease may be acute or insidious in its onset, and is typically a
chronic, remitting and relapsing, often febrile, illness. Injury to the skin,
joints, kidney, and serosal membranes is prominent. Virtually every other
organ in the body, however, may also be affected.
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SLE is a fairly common disease, with a prevalence that may be as high as
1 in 2500 in certain populations.
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SLE predominantly affects women, with a frequency of 1 in 700 among
women of childbearing age and a female-to-male ratio of 9 : 1 during the
reproductive age group of 17 through 55 years
Autoantibodies in SLE
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Antinuclear antibodies (ANAs). The most widely used method for detecting ANAs is indirect immunofluorescence,
which can identify antibodies that bind to a variety of nuclear antigens, including DNA, RNA, and proteins (collectively
called generic ANAs). The pattern of nuclear fluorescence suggests the type of antibody present in the patient’s
serum. Many basic patterns are recognized:
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diffuse nuclear staining usually reflects antibodies to chromatin, histones, and, occasionally, double-stranded
DNA.
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Rim or peripheral staining patterns are most often indicative of antibodies to double-stranded DNA and
sometimes to nuclear envelope proteins.
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Speckled pattern refers to the presence of uniform or variable-sized speckles. This is one of the most commonly
observed patterns of fluorescence and therefore the least specific. It reflects the presence of antibodies to nonDNA nuclear constituents such as Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens.
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Nucleolar pattern refers to the presence of a few discrete spots of fluorescence within the nucleus and
represents antibodies to RNA. This pattern is reported most often in patients with systemic sclerosis.
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Centromeric pattern. Patients with systemic sclerosis often contain antibodies specific for centromeres, which
give rise to this pattern.
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Though the pattern and sensitivity of the ANAs is controversial, the test remains in use.
Other autoantibodies:
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Directed against blood cells, such as red cells, platelets, and lymphocytes;
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Antiphospholipid antibodies are present in 30% to 40% of lupus patients. They are actually directed against
epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids. Some of
these antibodies interfere with in vitro clotting tests, such as partial thromboplastin time. Therefore, these
antibodies are sometimes referred to as lupus anticoagulant. Despite the observed clotting delays in vitro,
however, patients with antiphospholipid antibodies have complications related to excessive clotting (a
hypercoagulable state), such as thrombosis.
Patterns of ANAs
A.
B.
C.
D.
Diffuse
Rim
Speckled
Centromeric
Pathogenesis of SLE
The fundamental defect in SLE is a failure of the
mechanisms that maintain self-tolerance.
Genetic factors
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Family members of patients have an increased risk of developing SLE. As many as 20% of clinically
unaffected first-degree relatives of SLE patients reveal autoantibodies and other immunoregulatory
abnormalities.
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There is a higher rate of concordance (>20%) in monozygotic twins when compared with dizygotic twins (1%
to 3%).
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Studies of HLA associations support the concept that MHC genes regulate production of particular
autoantibodies. Specific alleles of the HLA-DQ locus have been linked to the production of anti–nuclear, and
antiphospholipid antibodies, although the relative risk is small.
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Some lupus patients have inherited deficiencies of early complement components, such as C2, C4, or C1q.
Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte
system, thus favoring tissue deposition. Knockout mice lacking C4 or certain complement receptors are also
prone to develop lupus-like autoimmunity. Various mechanisms have been invoked, including failure to clear
immune complexes and loss of B-cell self-tolerance. It has also been proposed that deficiency of C1q results
in defective phagocytic clearance of apoptotic cells. Many cells normally undergo apoptosis, and if they are
not cleared their nuclear components may elicit immune responses.
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Genome-wide association studies have identified several genetic loci that may be associated with the disease.
Many of these loci encode proteins involved in lymphocyte signaling and interferon responses, both of which
may play a role in lupus pathogenesis, as discussed later. The relative risk for each locus is small, and even
taken together these loci account for 20% or less of the genetic predisposition, suggesting an important role
for environmental factors, discussed later.
Immunologic factors
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Failure of self-tolerance in B cells results from defective elimination of self-reactive B cells in the bone marrow
or defects in peripheral tolerance mechanisms.
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CD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the production
of high-affinity pathogenic autoantibodies. The autoantibodies in SLE show characteristics of T cell-dependent
antibodies produced in germinal centers, and increased numbers of follicular helper T cells have been
detected in the blood of SLE patients.
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TLR (toll-like-receptor) engagement by nuclear DNA and RNA contained in immune complexes may activate
B lymphocytes. These TLRs function normally to sense microbial products, including nucleic acids. Thus, B
cells specific for nuclear antigens may get second signals from TLRs and may be activated, resulting in
increased production of antinuclear autoantibodies.
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Type I interferons play a role in lymphocyte activation in SLE. High levels of circulating type I interferons and a
molecular signature in blood cells suggesting exposure to these cytokines has been reported in SLE patients
and correlates with disease severity. Type I interferons are antiviral cytokines that are normally produced
during innate immune responses to viruses. It may be that nucleic acids engage TLRs on dendritic cells and
stimulate the production of interferons. In other words, self nucleic acids mimic their microbial counterparts.
How interferons contribute to the development of SLE is unclear; these cytokines may activate dendritic cells
and B cells and promote TH1 responses, all of which may stimulate the production of pathogenic
autoantibodies.
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Other cytokines that may play a role in unregulated B-cell activation include the TNF family member BAFF,
which promotes survival of B cells. In some patients and animal models, increased production of BAFF has
been reported, prompting attempts to block the cytokine or its receptor as therapy for SLE.
Environmental factors
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Exposure to ultraviolet (UV) light exacerbates the disease in
many individuals. UV irradiation may induce apoptosis in
cells and may alter the DNA in such a way that it becomes
immunogenic, perhaps because of enhanced recognition by
TLRs. In addition, UV light may modulate the immune
response, for example, by stimulating keratinocytes to
produce IL-1, a cytokine known to promote inflammation.
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The gender bias of SLE is partly attributable to actions of
sex hormones and partly related to genes on the X
chromosome, independent of hormone effects.
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Drugs such as hydralazine, procainamide, and Dpenicillamine can induce an SLE-like response in humans.
A Model for the
Pathogenesis of SLE.
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Immunologic abnormalities in SLE—both documented and postulated—are varied and complex.
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Potential model:
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UV irradiation and other environmental insults lead to the apoptosis of cells.
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Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens.
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Underlying abnormalities in B and T lymphocytes are responsible for defective tolerance, because of
which self-reactive lymphocytes survive and remain functional. These lymphocytes are stimulated by
nuclear self antigens, and antibodies are produced against the antigens.
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Complexes of the antigens and antibodies bind to Fc receptors on B cells and dendritic cells, and may be
internalized.
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The nucleic acid components engage TLRs and stimulate B cells to produce more autoantibodies. TLR
stimuli also activate dendritic cells to produce interferons and other cytokines, which further enhance the
immune response and cause more apoptosis.
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The net result is a cycle of antigen release and immune activation resulting in the production of highaffinity autoantibodies.
Model for the pathogenesis of systemic lupus
erythematosus.
In this hypothetical model, susceptibility genes interfere with the
maintenance of self-tolerance and external triggers lead to
persistence of nuclear antigens.
The result is an antibody response against self nuclear
antigens, which is amplified by the action of nucleic acids on
dendritic cells (DCs) and B cells, and the production of type 1
interferons. TLRs, Toll-like receptors.
Mechanisms of tissue injury
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Most of the systemic lesions are caused by immune complexes (type III hypersensitivity). DNA-anti-DNA complexes
can be detected in the glomeruli and small blood vessels. Low levels of serum complement (secondary to
consumption of complement proteins) and granular deposits of complement and immunoglobulins in the glomeruli
further support the immune complex nature of the disease. T cell infiltrates are also frequently seen in the kidneys,
but the role of these cells in tissue damage is not established.
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Autoantibodies specific for red cells, white cells, and platelets opsonize these cells and promote their phagocytosis
and lysis. There is no evidence that ANAs, which are involved in immune complex formation, can penetrate intact
cells. If cell nuclei are exposed, however, the ANAs can bind to them. In tissues, nuclei of damaged cells react with
ANAs, lose their chromatin pattern, and become homogeneous, to produce so-called LE bodies or hematoxylin
bodies. Related to this phenomenon is the LE cell, which is readily seen when blood is agitated in vitro. The LE cell is
any phagocytic leukocyte (blood neutrophil or macrophage) that has engulfed the denatured nucleus of an injured
cell. The demonstration of LE cells in vitro was used in the past as a test for SLE. With new techniques for detection
of ANAs, however, this test is now largely of historical interest. Sometimes, LE cells are found in pericardial or pleural
effusions in patients.
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Antiphospholipid antibody syndrome. Patients with antiphospholipid antibodies may develop venous and arterial
thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular
ischemia. This constellation of clinical features, in association with lupus, is referred to as the secondary
antiphospholipid antibody syndrome. The mechanisms of thrombosis are not defined, and antibodies against clotting
factors, platelets and endothelial cells have all been proposed as being responsible for thrombosis.
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The neuropsychiatric manifestations of SLE have been attributed to antibodies that react with neurons or receptors
for various neurotransmitters and cross the blood brain barrier. However, this is not established and mechanisms
involving other immune factors, such as cytokines, may also underlie the cognitive dysfunction and other CNS
abnormalities that are associated with SLE.
Type III Hypersensitivity
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Antigen-antibody complexes produce tissue damage mainly by eliciting
inflammation at the sites of deposition. The pathologic reaction is usually
initiated when antigen combines with antibody in the circulation, creating
immune complexes that typically deposit in vessel walls. Less frequently,
the complexes may be formed at sites where antigen has been “planted”
previously (called in situ immune complexes).
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The antigens that form immune complexes may be exogenous, such as a
foreign protein that is injected or produced by an infectious microbe, or
endogenous, if the individual produces antibody against self antigens
(autoimmunity).
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Immune complex–mediated diseases tend be systemic, but often
preferentially involve the kidney (glomerulonephritis), joints (arthritis), and
small blood vessels (vasculitis), all of which are common sites of immune
complex deposition.
Phases of type III HS
reactions
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Formation of immune complexes. Autoantibodies form antigen-antibody complexes.
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Deposition of immune complexes. In the next phase the circulating antigen-antibody
complexes are deposited in various tissues. The factors that determine whether immune
complex formation will lead to tissue deposition and disease are not fully understood, but the
major influences seem to be the characteristics of the complexes and local vascular
alterations. In general, complexes that are of medium size, formed in slight antigen excess,
are the most pathogenic. Organs where blood is filtered at high pressure to form other fluids,
like urine and synovial fluid, are sites where immune complexes become concentrated and
tend to deposit; hence, immune complex disease often affects glomeruli and joints.
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Inflammation and tissue injury. Once immune complexes are deposited in the tissues, they
initiate an acute inflammatory reaction. During this phase (approximately 10 days after
antigen administration), clinical features such as fever, urticaria, joint pains (arthralgias),
lymph node enlargement, and proteinuria appear. Wherever complexes deposit the tissue
damage is similar. The mechanisms of inflammation and injury were discussed above, in the
discussion of antibody-mediated injury. The resultant inflammatory lesion is termed vasculitis
if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it
occurs in the joints, and so on.
Immune complex disease.
The sequential phases in the induction of systemic
immune complex–mediated diseases (type III
hypersensitivity).
Blood Vessels.
An acute necrotizing vasculitis involving capillaries, small arteries and arterioles may be present in any tissue. The arteritis is characterized by fibrinoid
deposits in the vessel walls. In chronic stages, vessels undergo fibrous thickening with luminal narrowing.
Kidney.
Up to 50% of SLE patients have clinically significant renal involvement. All of the glomerular lesions described later are the result of deposition of immune
complexes that are regularly present in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus. Both in situ
formation and deposition of preformed circulating immune complexes may contribute to the injury, but the reason for the wide spectrum of histopathologic
lesions (and clinical manifestations) in patients with lupus nephritis remains uncertain.
The kidney virtually always shows some evidence of renal abnormality if examined by electron microscopy and immunofluorescence. According to the
currently accepted classification, six patterns of glomerular disease are seen in SLE. It should be noted that there is some overlap within these classes and
over time lesions may evolve from one class to another. Thus, the exact percentage of patients with each of the six classes of lesions is difficult to determine.
Suffice it to say that Class I is the least common and class IV is the most common pattern.
Minimal mesangial lupus nephritis (class I) is very uncommon, and is characterized by immune complex deposition in the mesangium, identified by
immunoflourescence and by electron microscopy, but without structural changes by light microscopy.
Mesangial proliferative lupus nephritis (class II) is characterized by mesangial cell proliferation, often accompanied by accumulation of mesangial matrix, and
granular mesangial deposits of immunoglobulin and complement without involvement of glomerular capillaries.
Focal lupus nephritis (class III) is defined by involvement of fewer than 50% of all glomeruli. The lesions may be segmental (affecting only a portion of the
glomerulus) or global (involving the entire glomerulus). Affected glomeruli may exhibit swelling and proliferation of endothelial and mesangial cells associated
with leukocyte accumulation, capillary necrosis, and hyaline thrombi. There is also often extracapillary proliferation associated with focal necrosis and crescent
formation (Fig. 6-26A). The clinical presentation ranges from mild hematuria and proteinuria to acute renal insufficiency. Red cell casts in the urine are
common when the disease is active. Some patients progress to diffuse glomerulonephritis. The active (or proliferative) inflammatory lesions can heal
completely or lead to chronic global or segmental glomerular scarring.
Diffuse lupus nephritis (class IV) is the most common and severe form of lupus nephritis. The lesions are similar to those in class III, but differ in extent;
typically, in class IV nephritis half or more of the glomeruli are affected. As in class III, the lesions may be segmental or global and on the basis of this, it can
be subclassified as Class IV segmental ( IV-S) or Class IV global (IV-G). Involved glomeruli show proliferation of endothelial, mesangial and epithelial cells
(Fig. 6-26B), with the latter producing cellular crescents that fill Bowman’s space (Chapter 20). Subendothelial immune complex deposits may create a
circumferential thickening of the capillary wall, forming “wire loop” structures on light microscopy (Fig. 6-26C). Immune complexes can be readily detected by
electron microscopy (Fig. 6-26D) and immunofluorescence (Fig. 6-26E). Lesions may progress to scarring of glomeruli. Patients with diffuse glomerulonephritis
are usually symptomatic, showing hematuria as well as proteinuria. Hypertension and mild to severe renal insufficiency are also common.
Membranous lupus nephritis (class V) is characterized by diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes, similar
to idiopathic membranous nephropathy, described in Chapter 20. The immune complexes are usually accompanied by increased production of basement
membrane-like material. This lesion is usually accompanied by severe proteinuria or nephrotic syndrome, and may occur concurrently with focal or diffuse
lupus nephritis.
Advanced sclerosing lupus nephritis (class VI) is characterized by sclerosis of more than 90% of the glomeruli, and represents end-stage renal disease.
Changes in the interstitium and tubules are frequently present in lupus nephritis patients. Rarely, tubulointerstitial lesions may be the dominant abnormality.
Discrete immune complexes similar to those in glomeruli are present in the tubular or peritubular capillary basement membranes in many lupus nephritis
patients, but the clinical significance of these extraglomerular deposits is not established. Often, there are well-organized B-cell follicles in the interstitium, with
plasma cells that may be sources of autoantibodies.
Lupus nephritis.
A, Focal proliferative glomerulonephritis,
with two focal necrotizing lesions at the
11 O’clock and 2 O’clock positions (H&E
stain). Extracapillary proliferation is not
prominent in this case.
B, Diffuse proliferative
glomerulonephritis. Note the marked
increase in cellularity throughout the
glomerulus (H&E stain).
C, Lupus nephritis showing a glomerulus
with several “wire loop” lesions
representing extensive subendothelial
deposits of immune complexes (periodic
acid-Schiff stain). D, Electron
micrograph of a renal glomerular
capillary loop from a patient with SLE
nephritis. Subendothelial dense deposits
(arrowheads) correspond to “wire loops”
seen by light microscopy. B (with arrow)
refers to the basement membrane.
E, Deposition of IgG antibody in a
granular pattern, detected by
immunofluorescence. B, Basement
membrane; End, endothelium; Ep,
epithelial cell with foot processes; Mes,
mesangium; RBC, red blood cell in
capillary lumen; US, urinary space.
Systemic lupus erythematosus
involving the skin.
A, An H&E-stained section shows
liquefactive degeneration of the
basal layer of the epidermis and
edema at the dermoepidermal
junction.
B, An immunofluorescence
micrograph stained for IgG reveals
deposits of Ig along the
dermoepidermal junction.