Autoimmune disesse Flashcards
1
Q
three requirements
should be met before a disorder is categorized as truly caused
by autoimmunity
A
(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
2
Q
Disorders in which chronic
inflammation is a prominent component are sometimes grouped
under
A
immune-mediated inflammatory diseases; these may be
autoimmune or the immune response may be directed against
normally harmless microbes such as gut commensal bacteria
3
Q
Organ-Specific AI
A
Diseases Mediated by Antibodies Autoimmune hemolytic anemia Autoimmune thrombocytopenia Autoimmune atrophic gastritis of pernicious anemia Myasthenia gravis Graves disease Goodpasture syndrome
Diseases Mediated by T Cells*
Type 1 diabetes mellitus
Multiple sclerosis
Diseases Postulated to Be Autoimmune
Inflammatory bowel diseases (Crohn disease, ulcerative colitis)
Primary biliary cirrhosis
Autoimmune (chronic active) hepatitis
4
Q
Systemic AI
A
SLE (Antibody mediated)
RA (T cell mediated)
Polyarteritis Nodosa (postulated to be AI) Inflammatory myopathy (Postulated to be AI
5
Q
Immunologic Tolerance
A
Immunologic tolerance is the phenomenon of
unresponsiveness to an antigen-induced by exposure of
lymphocytes to that antigen
6
Q
Self-tolerance
A
refers to lack of
responsiveness to an individual’s own antigens, and it underlies
our ability to live in harmony with our cells and tissues. Because
the antigen receptors of lymphocytes are generated by somatic
recombination of genes in a random fashion
7
Q
Central Tolerance
A
In this process, 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.
8
Q
• In developing T cells
A
random somatic gene rearrangements
generate diverse TCRs. Such antigen-independent TCR generation produces many lymphocytes that express highaffinity receptors for self antigens.
When immature
lymphocytes encounter the antigens in the thymus, many of the
cells die by apoptosis.
This process, called negative selection or
deletion is responsible for eliminating self-reactive lymphocytes from the T-cell pool.
9
Q
A wide variety of autologous
protein antigens, including antigens thought to be restricted to
peripheral tissues, are processed and presented by
A
thymic
antigen-presenting cells in association with self MHC molecules
and can, therefore, be recognized by potentially self-reactive T
cells
10
Q
AIRE
A
(autoimmune regulator);
stimulates expression of some “peripheral tissue-restricted” self-antigens
in the thymus and is thus critical for deletion of immature T cells specific for these antigens.
Mutations in the AIRE gene
are the cause of an autoimmune polyendocrinopathy Ch.24
11
Q
developing B cells
A
strongly recognize self antigens in the
bone marrow, many of the cells reactivate the machinery of
antigen receptor gene rearrangement and begin to express new
antigen receptors, not specific for self antigens. This process is
called receptor editing
12
Q
How many cells are thought to have undergone Receptor editing during maturation?
A
it is estimated that a quarter to half of
all B cells in the body may have undergone receptor editing
during their maturation. If receptor editing does not occur, the
self-reactive cells undergo apoptosis, thus purging potentially
dangerous lymphocytes from the mature pool
13
Q
Peripheral Tolerance
A
Several mechanisms silence potentially autoreactive T and B
cells in peripheral tissues; these are best defined for T cells.
14
Q
Anergy
A
Lymphocytes that recognize self antigens may be rendered functionally unresponsive, a phenomenon called
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
15
Q
activation of antigen-specific
T cells require two signals
A
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
16
Q
second signals are provided by certain T cell-associated
molecules, such as
A
CD28, that bind to their ligands (the
costimulators B7-1 and B7-2) on APCs.
17
Q
If the antigen is
presented to T cells without adequate levels of costimulators
A
cells become anergic.
18
Q
is that T
cells that recognize self antigens receive an inhibitory signal
from receptors that are structurally homologous to
A
CD28 but
serve the opposite functions
19
Q
Two of these inhibitory receptors
are
A
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
20
Q
CTLA-4 has higher affinity for
A
B7 molecules
than does CD28, CTLA-4 may be preferentially engaged when
the levels of B7 are low, as when APCs are presenting self
antigens.
21
Q
microbial products elicit innate immune
reactions, during which
A
B7 levels on APCs increase and the
low-affinity receptor CD28 is engaged more. Thus, the affinities
of the activating and inhibitory receptors and the level of
expression of B7 may determine the outcome of T cell antigen
recognition.
22
Q
CTLA-4 or PD-1 is knocked out
A
develop autoimmune
diseases
23
Q
antibodies that
block CTLA-4 and PD-1 for
A
tumor immunotherapy—by removing
the brakes on the immune response, these antibodies promote
responses against tumors.
24
Q
Suppression by regulatory T cells. A population of T cells
called regulatory T cells functions to prevent immune
reactions against
A
self antigens
25
Regulatory T cells develop
| mainly in the
thymus, as a result of recognition of self antigens
(Fig. 6-21), but they may also be induced in peripheral
lymphoid tissues
26
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. Both IL-2 and FOXP3 are required for the
development and maintenance of functional CD4+ regulatory T
cells.
27
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, Xlinked).
28
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
29
Recent genome-wide association studies
have revealed that polymorphisms in the CD25 gene are
associated with
multiple sclerosis and other autoimmune
diseases, raising the possibility of a regulatory T-cell defect
contributing to these diseases
30
T Cell 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. 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
31
Regulatory T cells may play a role in the acceptance of
fetus
32
There is
emerging evidence that regulatory T cells prevent immune
reactions against
fetal antigens that are inherited from the
father and therefore foreign to the mother. In line with this
idea, during evolution, placentation appeared simultaneously
with the ability to stably express the Foxp3 transcription factor.
33
Deletion by apoptosis
T cells that recognize self
antigens may receive signals that promote their death by
apoptosis
34
Two mechanisms of deletion of mature T cells have
| been proposed, based mainly on studies in mice
It is postulated
that if T cells recognize self antigens, they may express a proapoptotic 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). Unopposed Bim triggers apoptosis by the
mitochondrial pathway
A second mechanism of
activation-induced death of CD4+ T cells and B cells involves
the Fas-Fas ligand system. Lymphocytes as well as many other
cells express the death receptor Fas (CD95), a member of the
TNF-receptor family. Fas ligand (FasL), a membrane protein
that is structurally homologous to the cytokine TNF, is
expressed mainly on activated T lymphocytes. The engagement
of Fas by FasL induces apoptosis of activated T cells (
35
In humans a similar disease is
| caused by mutations in the FAS gene
autoimmune lymphoproliferative syndrome (ALPS).
36
Some antigens are hidden (sequestered) from the immune
| system, because
hidden (sequestered) from the immune
system, because the tissues in which these antigens are located
do not communicate with the blood and lymph. As a result, self
antigens in these tissues fail to elicit immune responses and are
essentially ignored by the immune system. This is believed to
be the case for the testis, eye, and brain, all of which are called
immune-privileged sites
37
Autoimmunity
arises from a combination of the
inheritance of susceptibility genes, which may contribute
to the breakdown of self-tolerance, and environmental
triggers, such as infections and tissue damage, which
promote the activation of self-reactive lymphocytes
38
Defective tolerance or regulation
Fundamental to the
development of autoimmune diseases is a failure of the
mechanisms that maintain self-tolerance
39
• 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. If these changes lead to the display of
antigenic epitopes that are not expressed normally, the immune
system may not be tolerant to these epitopes, thus allowing
anti-self responses to develop.
40
Inflammation or an initial innate immune response
innate immune response is a strong
stimulus for the subsequent activation of lymphocytes and the
generation of adaptive immune responses. Microbes or cell
injury may elicit local inflammatory reactions resembling innate
immune responses, and these may be critical inducers of the
autoimmune disease.
41
Role of Susceptibility Genes
Most autoimmune diseases are complex multigenic
disorders
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.
42
Association of HLA Alleles with Disease
Among the genes known to be associated with
autoimmunity, the greatest contribution is that of HLA
genes
43
The most striking of these associations is between ankylosing spondylitis
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
44
Association of Non-MHC Genes with Autoimmune
| Diseases
Genome-wide association studies and family studies have shown
that multiple non-MHC genes are associated with various
autoimmune diseases
45
Polymorphisms in a gene called PTPN22,
protein tyrosine phosphatase, are associated with rheumatoid
arthritis, type 1 diabetes, and several other autoimmune
diseases
46
the gene
| that is most frequently implicated in autoimmunity
PTPN22,
47
Polymorphisms in the gene for NOD2 are associated with
Crohn disease, a form of inflammatory bowel disease, especially
in certain ethnic populations. NOD2, a member of the NOD-like
receptor (NLR) family (discussed earlier), is a cytoplasmic
sensor of microbes that is expressed in intestinal epithelial and
other cells
48
Polymorphisms in the genes encoding the IL-2 receptor (CD25)
| and IL-7 receptor α chains are associated with
multiple
sclerosis and other autoimmune diseases. These cytokines may
control the maintenance of regulatory T cells.
49
PTPN22
RA, T1D, IBD
Protein tyrosine phosphatase, may affect signaling in lymphocytes and may alter negative
selection or activation of self-reactive T cells
50
IL23R
IBD, PS (Psoriasis), AS (Ankyl. Spond)
Receptor for the TH17-inducing cytokine IL-23; may alter differentiation of CD4+ T cells into
pathogenic TH17effector cells
51
CTLA4
T1D, RA
Inhibits T cell responses by terminating activation and promoting activity of regulatory T cells;
may interfere with self-tolerance
52
IL2RA
MS, T1D
α chain of the receptor for IL-2, which is a growth and survival factor for activated and
regulatory T cells; may affect development of effector cells and/or regulation of immune
responses
53
NOD2
IBD
Cytoplasmic sensor of bacteria expressed in Paneth and other intestinal epithelial cells; may
control resistance to gut commensal bacteria
54
ATG16
IBD
Involved in autophagy; possible role in defense against microbes and maintenance of epithelial
barrier function
55
IRF5, IFIH1
SLE
Role in type I interferon production; type I IFN is involved in the pathogenesis of SLE
56
Role of Infections
Autoimmune reactions may be triggered by infections
57
Two mechanisms of Infections
First, 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
Second, 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
58
molecular mimicry
Immune
responses against the microbial antigens may result in the
activation of self-reactive lymphocytes
A clear example of such mimicry is
rheumatic heart disease, in which antibodies against
streptococcal proteins cross-react with myocardial proteins and
cause myocarditis
59
Epstein-Barr virus
| (EBV) and HIV
cause polyclonal B-cell activation, which may
| result in production of autoantibodies.
60
Infections may protect against some autoimmune
| diseases
Although the role of infections in triggering autoimmunity has received a great deal of attention, recent
epidemiologic studies suggest that the incidence of autoimmune
diseases is increasing in developed countries as infections are
better controlled. In some animal models (e.g., of type 1 diabetes) infections greatly reduce the incidence of disease
61
General Features of Autoimmune
| Disease
Autoimmune diseases tend to be chronic, sometimes with relapses and remissions, and the damage is often
progressive. One reason for the chronicity is that the immune
system contains many intrinsic amplification loops that allow
small numbers of antigen-specific lymphocytes to accomplish
their task of eradicating complex infections.
62
The clinical and pathologic manifestations of an
| autoimmune disease are determined by
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.
63
CD8+ CTLs contribute to the 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.
64
Systemic Lupus Erythematosus (SLE)
SLE is an autoimmune disease involving multiple organs,
characterized by a vast array of autoantibodies,
particularly antinuclear antibodies (ANAs), in which injury
is caused mainly by deposition of immune complexes and
binding of antibodies to various cells and tissues.
65
SLE is a
| fairly common disease, with a prevalence that may be as high as
1 in 2500 in certain populations. Similar to many autoimmune
diseases, 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
66
female-to-male ratio is only
2 : 1 for
disease developing during childhood or after the age of 65. The
prevalence of the disease is 2- to 3-fold higher in blacks and
Hispanics than in whites
67
The hallmark of SLE is the
production of autoantibodies
68
Antinuclear antibodies (ANAs)
(1) antibodies to DNA,
(2) antibodies to histones,
(3) antibodies to nonhistone proteins bound to RNA, and
(4) antibodies to
nucleolar antigens.
69
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
70
Four basic patterns are
```
Homogeneous or diffuse nuclear staining
Rim or peripheral staining
Speckled pattern
Nucleolar pattern
Centromeric pattern
```
71
Homogeneous or diffuse nuclear staining
reflects
| antibodies to chromatin, histones, and, occasionally, double-stranded DNA
72
Rim or peripheral staining
patterns are most often indicative of
antibodies to double-stranded DNA and sometimes to nuclear
envelope proteins.
73
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 non-DNA nuclear
constituents such as Sm antigen, ribonucleoprotein, and SS-A
and SS-B reactive antigens.
74
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.
75
Centromeric pattern.
Patients with systemic sclerosis often
contain antibodies specific for centromeres, which give rise to
this pattern
76
Antibodies to double-stranded DNA and the so-called
| Smith (Sm) antigens are
diagnostic of SLE
77
Antiphospholipid antibodies
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
78
prothrombin, annexin V, β2
glycoprotein I, protein S, and protein C. Antibodies against the
phospholipid-β2
-glycoprotein complex also bind to cardiolipin antigen, used in
syphilis serology
79
Why do SLE patients have a false-positive test for Syphilis?
prothrombin, annexin V, β2
glycoprotein I, protein S, and protein C. Antibodies against the
phospholipid-β2
-glycoprotein complex also bind to cardiolipin
antigen, used in syphilis serology
80
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
81
Etiology and Pathogenesis of SLE
The fundamental defect in SLE is a failure of the
mechanisms that maintain self-tolerance. Although what
causes this failure of self-tolerance remains unknown, as is true
of most autoimmune diseases, both genetic and environmental
factors play a role.
82
Genetic Factors of SLE
SLE is a genetically complex disease with contributions from
MHC and multiple non-MHC genes. Many lines of evidence
support a genetic predisposition
83
Family members of patients have an increased risk of
| developing SLE
As many as 20% of clinically unaffected firstdegree relatives of SLE patients reveal autoantibodies and
other immunoregulatory abnormalities
84
Immunologic Factors of ALE
Recent studies in animal models and patients have revealed
several immunologic aberrations that collectively may result in
the persistence and uncontrolled activation of self-reactive
lymphocytes
85
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.
86
CD4+ helper T cells
specific for nucleosomal antigens also
escape tolerance and contribute to the production of highaffinity 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.
87
TLR engagement by nuclear DNA and RNA
ontained 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
88
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.
89
Type I interferons are antiviral cytokines
| that are normally produced during
innate immune responses to
| viruses.
90
Environmental Factors for SLE`
There are many indications that environmental factors must also
be involved in the pathogenesis of SLE
91
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
92
gender bias of SLE
partly attributable to actions of sex
hormones and partly related to genes on the X chromosome,
independent of hormone effects.
93
Drugs
hydralazine, procainamide, and d-penicillamine
| can induce an SLE-like response in humans.
94
Most of the systemic lesions are caused by immune
| complexes
(type III hypersensitivity
95
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.
96
T cell
| infiltrates are also frequently seen
the kidneys, but the role
| of these cells in tissue damage is not established
97
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.
98
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,
99
secondary 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
100
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
101
Hematologic
100
102
Arthritis, arthralgia or myalgia
80-90
103
Skin
85
104
Fever
55-85
105
Fatigue
80-100
106
Weight loss
60
107
Renal
50-70
108
Neuropsychiatric
25-35
109
Pleuritis
45
110
Pericarditis
25
111
GI
20
112
Raynaud P
15-40
113
Ocular
5-15
114
Periph. Neuropathy
15
115
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.
116
Kidney
Up to 50% of SLE patients have clinically significant
renal involvement
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.
117
Minimal mesangial lupus nephritis (class I)
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
118
Mesangial proliferative lupus nephritis (class II)
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
119
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
120
Membranous lupus nephritis (class V)
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.
121
Advanced sclerosing lupus nephritis (class VI)
characterized by sclerosis of more than 90% of the
| glomeruli, and represents end-stage renal disease.
122
Changes in the interstitium and tubules are
| frequently present in lupus nephritis patients. Rarely
tubulointerstitial lesions may be the dominant
| abnormality
123
Skin
Characteristic erythema affects the face along the
bridge of the nose and cheeks (the “butterfly” rash) in
approximately 50% of patients, but a similar rash may also be seen on the extremities and trunk. Urticaria, bullae, maculopapular lesions, and ulcerations also occur. Exposure to sunlight incites or accentuates the erythema. Histologically the involved areas show vacuolar degeneration of the basal layer of the epidermis
124
In the dermis
there is variable
edema and perivascular inflammation. Vasculitis with
fibrinoid necrosis may be prominent.
Immunofluorescence microscopy shows deposition of
immunoglobulin and complement along the
dermoepidermal junction (Fig. 6-27B), which may also
be present in uninvolved skin. This finding is not
diagnostic of SLE and is sometimes seen in
scleroderma or dermatomyositis
125
Joints.
Joint involvement is typically a nonerosive synovitis
with little deformity, which contrasts with rheumatoid
arthritis.
126
Central Nervous System
Neuropsychiatric symptoms of SLE have often been
ascribed to acute vasculitis, but in histologic studies of
the nervous system in such patients significant
vasculitis is rarely present. Instead, noninflammatory
occlusion of small vessels by intimal proliferation is
sometimes noted, which may be due to endothelial
damage by autoantibodies or immune complexes
127
Pericarditis and Other Serosal Cavity
| Involvement
Inflammation of the serosal lining membranes may be
acute, subacute, or chronic. During the acute phases,
the mesothelial surfaces are sometimes covered with
fibrinous exudate. Later they become thickened,
opaque, and coated with a shaggy fibrous tissue that
may lead to partial or total obliteration of the serosal
cavity. Pleural and pericardial effusions may be
present.
128
Cardiovascular system involvement may manifest
| as damage
e to any layer of the heart. Symptomatic or
asymptomatic pericardial involvement is present in up
to 50% of patients.
129
Myocarditis, or mononuclear cell
| infiltration
less common and may cause resting
tachycardia and electrocardiographic abnormalities.
Valvular abnormalities, primarily of the mitral and
aortic valves, manifest as diffuse leaflet thickening
that may be associated with dysfunction (stenosis
and/or regurgitation). Valvular (or so-called LibmanSacks) endocarditis was more common prior to the
widespread use of steroids
130
nonbacterial
verrucous endocarditis takes the form of single or
multiple
1- to 3-mm warty deposits on any heart valve,
distinctively on either surface of the leaflets (Fig. 6-
28). By comparison, the vegetations in infective
endocarditis are considerably larger, and those in
rheumatic heart disease (Chapter 12) are smaller and
confined to the lines of closure of the valve leaflets
131
Risk factors for
atherosclerosis, including hypertension, obesity, and
hyperlipidemia, are more commonly present in
SLE
patients than in the population at large. In addition,
immune complexes and antiphospholipid antibodies
may cause endothelial damage and promote
atherosclerosis.
132
Spleen
Splenomegaly, capsular thickening, and follicular
hyperplasia are common features. Central penicilliary
arteries may show concentric intimal and smooth
muscle cell hyperplasia, producing so-called onionskin lesions.
133
Lungs
In addition to pleuritis and pleural effusions, which
are present in almost 50% of patients, in some cases,
there is chronic interstitial fibrosis and secondary
pulmonary hypertension. None of these changes is
specific for SLE
134
Other Organs and Tissues
LE, or hematoxylin, bodies in the bone marrow or
other organs are strongly indicative of SLE. Lymph
nodes may be enlarged with hyperplastic follicles or
even demonstrate necrotizing lymphadenitis.
135
Clinical Features of SLE
a butterfly rash over
the face, fever, pain but no deformity in one or more peripheral
joints (feet, ankles, knees, hips, fingers, wrists, elbows,
shoulders), pleuritic chest pain, and photosensitivity. In many
patients, however, the presentation of SLE is subtle and
puzzling, taking forms such as a febrile illness of unknown
origin, abnormal urinary findings, or joint disease masquerading
as rheumatoid arthritis or rheumatic fever
136
“Generic” ANAs
detected by immunofluorescence assays, are found in virtually
100% of patients, but these are not specific for SLE. A variety of
clinical findings may point toward renal involvement, including
hematuria, red cell casts, proteinuria, and in some cases the
classic nephrotic syndrome
137
Laboratory evidence of
some hematologic derangement is seen in virtually every case,
but in some
anemia or thrombocytopenia may be the
presenting manifestation as well as the dominant clinical
problem. In still others, mental aberrations, including psychosis
or convulsions, or coronary artery disease may be prominent
clinical problems
138
Patients with SLE are also prone to infections
presumably because of their underlying immune dysfunction and
treatment with immunosuppressive drugs.
139
The course of the disease is
variable and unpredictable. Rare
acute cases result in death within weeks to months. More often,
with appropriate therapy, the disease is characterized by flareups and remissions spanning a period of years or even dec
140
During acute flare-ups
increased formation of immune
complexes results in complement activation, often leading to
hypocomplementemia. Disease flares are usually treated with
corticosteroids or other immunosuppressive drugs.
141
Chronic Discoid Lupus Erythematosus.
Chronic discoid lupus erythematosus is a disease in which the
skin manifestations may mimic SLE, but systemic manifestations
are rare. It is characterized by the presence of skin plaques
showing varying degrees of edema, erythema, scaliness,
follicular plugging, and skin atrophy surrounded by an elevated
erythematous border. The face and scalp are usually affected,
but widely disseminated lesions occasionally occur. The disease
is usually confined to the skin, but 5% to 10% of patients with
discoid lupus erythematosus develop multisystem manifestations
after many years. Conversely, some patients with SLE may have
prominent discoid lesions in the skin. Approximately 35% of
patients show a positive test for generic ANAs, but antibodies to
double-stranded DNA are rarely present. Immunofluorescence
studies of skin biopsy specimens show deposition of
immunoglobulin and C3 at the dermoepidermal junction similar
to that in SLE.
142
Subacute Cutaneous Lupus Erythematosus
This condition also presents with predominant skin involvement
and can be distinguished from chronic discoid lupus
erythematosus by several criteria. The skin rash in this disease
tends to be widespread, superficial, and nonscarring, although
scarring lesions may occur in some patients. Most patients have
mild systemic symptoms consistent with SLE. Furthermore,
there is a strong association with antibodies to the SS-A antigen
and with the HLA-DR3 genotype. Thus, the term subacute
cutaneous lupus erythematosus seems to define a group
intermediate between SLE and lupus erythematosus localized
only to skin.
143
Drug-Induced Lupus Erythematosus
A lupus erythematosus-like syndrome may develop in patients
receiving a variety of drugs, including hydralazine,
procainamide, isoniazid, and d-penicillamine, to name only a few.
Somewhat surprisingly, anti-TNF therapy, which is effective in
rheumatoid arthritis and other autoimmune diseases, can also
cause drug-induced lupus
144
Persons with the HLA-DR4 allele
at a greater risk
of developing a lupus erythematosus-like syndrome after
administration of hydralazine, whereas those with HLA-DR6 (but
not DR4) are at high risk with procainamide. The disease remits
after withdrawal of the offending drug.
145
Rheumatoid Arthritis
Rheumatoid arthritis is a chronic inflammatory disease that
affects primarily the joints but may involve extraarticular tissues
such as the skin, blood vessels, lungs, and heart. Abundant
evidence supports the autoimmune nature of the disease.
146
Sjögren Syndrome
```
Sjögren syndrome is a chronic disease characterized by
dry eyes (keratoconjunctivitis sicca) and dry mouth
(xerostomia) resulting from immunologically mediated
destruction of the lacrimal and salivary glands
```
147
The characteristic decrease in tears and saliva
(sicca syndrome)
is the result of lymphocytic infiltration and fibrosis of the
lacrimal and salivary glands. The infiltrate contains
predominantly activated CD4+ helper T cells and some B cells,
including plasma cell
148
About 75% of patients have
rheumatoid
factor (an antibody reactive with self IgG) whether or not
coexisting rheumatoid arthritis is present. ANAs are detected in
50% to 80% of patients by immunofluorescence assay
149
Most important, however, are antibodies
| directed against two ribonucleoprotein antigens,
SS-A (Ro) and
SS-B (La) (Table 6-10), which can be detected in as many as 90%
of patients by sensitive techniques. These antibodies are thus
considered serologic markers of the disease.
150
Patients with high
| titers of antibodies to SS-A
likely to have early disease
onset, longer disease duration, and extraglandular
manifestations, such as cutaneous vasculitis and nephritis.
These autoantibodies are also present in a smaller percentage of
patients with SLE and hence are not diagnostic of Sjögren
syndrome.
151
The earliest histologic finding in
| both the major and the minor salivary glands is
periductal and perivascular lymphocytic infiltration.
Eventually the lymphocytic infiltrate becomes
extensive (Fig. 6-29), and in the larger salivary glands
lymphoid follicles with germinal centers may be seen
152
The ductal lining epithelial cells may show
hyperplasia, thus obstructing the ducts. Later there is
atrophy of the acini, fibrosis, and hyalinization; still
later in the course atrophy and replacement of
parenchyma with fat are seen. In some cases the
lymphoid infiltrate may be so intense as to give the
appearance of a lymphoma
153
e patients are
| at high risk for development Sjogren
B-cell lymphomas, and
molecular assessments of clonality may be necessary
to distinguish intense reactive chronic inflammation
from early involvement by lymphoma
154
The lack of tears leads to
drying of the corneal
epithelium, which becomes inflamed, eroded, and
ulcerated; the oral mucosa may atrophy, with
inflammatory fissuring and ulceration; and dryness
and crusting of the nose may lead to ulcerations and
even perforation of the nasal septum
155
Sjögren syndrome occurs most commonly in women between the
| ages of
50 and 60. As might be expected, symptoms result from
inflammatory destruction of the exocrine glands. The
keratoconjunctivitis produces blurring of vision, burning, and
itching, and thick secretions accumulate in the conjunctival sac
156
xerostomia
results in difficulty in swallowing solid foods, a
decrease in the ability to taste, cracks and fissures in the mouth,
and dryness of the buccal mucosa. Parotid gland enlargement is
present in half the patients; dryness of the nasal mucosa,
epistaxis, recurrent bronchitis, and pneumonitis are other
symptoms.
157
Manifestations of extraglandular disease are seen in
Manifestations of extraglandular disease are seen in
158
contrast to SLE, glomerular lesions are extremely rare in
Sjögren syndrome. Defects of tubular function, however,
including renal tubular acidosis, uricosuria, and phosphaturia,
are often seen and are associated histologically with
tubulointerstitial nephritis
159
The combination of lacrimal and salivary gland inflammatory
| involvement was once called
Mikulicz disease. The name has
now been replaced by Mikulicz syndrome, broadened to include
lacrimal and salivary gland enlargement from any cause,
including sarcoidosis, lymphoma, and other tumors. Biopsy of
the lip (to examine minor salivary glands) is essential for the
diagnosis of Sjögren syndrome
160
Systemic Sclerosis (Scleroderma)
Systemic sclerosis is characterized by: (1) chronic
inflammation thought to be the result of autoimmunity,
(2) widespread damage to small blood vessels, and (3)
progressive interstitial and perivascular fibrosis in the
skin and multiple organs.
161
systemic
sclerosis has been recognized by classifying the disease into two
major categories
diffuse scleroderma
| limited scleroderma
162
limited scleroderma
which the skin involvement is often confined to fingers,
forearms, and face. Visceral involvement occurs late; hence, the
clinical course is relatively benign. Some patents with the
limited disease also develop a combination of calcinosis,
Raynaud phenomenon, esophageal dysmotility, sclerodactyly,
and telangiectasia, called the CREST syndrome. Several other
variants and related conditions
163
diffuse scleroderma,
characterized by
widespread skin involvement at onset, with rapid progression
and early visceral involvement
164
Autoimmunity in Scleroderma
It is proposed that CD4+ T cells responding to
an as yet unidentified antigen accumulate in the skin and
release cytokines that activate inflammatory cells and
fibroblasts. Although inflammatory infiltrates are typically
sparse in the skin of patients with systemic sclerosis, activated
CD4+ T cells can be found in many patients, and TH2 cells have
been isolated from the skin. Several cytokines produced by
these T cells, including TGF-β and IL-13, can stimulate
transcription of genes that encode collagen and other
extracellular matrix proteins (e.g., fibronectin) in fibroblasts.
Other cytokines recruit leukocytes and propagate the chronic
inflammation.
165
Vascular damage. in Scleroderma
Microvascular disease is consistently
present early in the course of systemic sclerosis and may
be the initial lesion.
the digital arteries of patients with systemic sclerosis. Capillary
dilation with leaking, as well as destruction, is also common.
Nailfold capillary loops are distorted early in the course of
disease, and later they disappear. Telltale signs of endothelial
activation and injury (e.g., increased levels of von Willebrand
factor) and increased platelet activation (increased percentage
of circulating platelet aggregates) have also been noted.
166
Repeated cycles of
endothelial injury followed by platelet aggregation lead to
release of platelet and endothelial factors (e.g., PDGF, TGF-β)
perivascular fibrosis.
167
Fibrosis
The progressive fibrosis characteristic of the disease
may be the culmination of multiple abnormalities, including the
accumulation of alternatively activated macrophages, actions of
fibrogenic cytokines produced by infiltrating leukocytes,
hyperresponsiveness of fibroblasts to these cytokines, and
scarring following upon ischemic damage caused by the
vascular lesions
168
Skin morphology in Scleroderma
A great majority of patients have diffuse, sclerotic atrophy of the skin, which usually begins in the fingers and distal regions of the upper extremities and extends proximally to involve the upper arms, shoulders, neck, and face. Histologically, there are edema and perivascular infiltrates containing CD4+ T cells, together with swelling and degeneration of collagen fibers, which become eosinophilic
169
Capillaries
and small arteries (150 to 500 µm in diameter) may
show
thickening of the basal lamina, endothelial cell
damage, and partial occlusion. With progression of the
disease, there is increasing fibrosis of the dermis,
which becomes tightly bound to the subcutaneous
structures.
170
Focal
and sometimes diffuse subcutaneous calcifications
may develop, especially in patients with the
CREST
syndrome. In advanced stages the fingers take on a
tapered, clawlike appearance with limitation of motion
in the joints, and the face becomes a drawn mask
171
Alimentary Tract. in Sclero`
The alimentary tract is affected in approximately 90%
of patients. Progressive atrophy and collagenous
fibrous replacement of the muscularis may develop at
any level of the gut but are most severe in the
esophagus
172
The lower two thirds of the esophagus
| often develops
rubber-hose–like inflexibility. The
associated dysfunction of the lower esophageal
sphincter gives rise to gastroesophageal reflux and its
complications, including Barrett metaplasia
173
Loss of villi and
microvilli in the small bowel is the anatomic basis for
the malabsorption syndrome
Loss of villi and
microvilli in the small bowel is the anatomic basis for
the malabsorption syndrome
174
The mucosa is thinned and may be
| ulcerated,
and there is excessive collagenization of the
| lamina propria and submucosa.
175
Lungs
The lungs are involved in more than 50% of
individuals with systemic sclerosis. This involvement
may manifest as pulmonary hypertension and
interstitial fibrosis. Pulmonary vasospasm, secondary
to pulmonary vascular endothelial dysfunction, is
considered important in the pathogenesis of
pulmonary hypertension. Pulmonary fibrosis, when
present, is indistinguishable from that seen in
idiopathic pulmonary fibrosis
176
Heart
Pericarditis with effusion, myocardial fibrosis, and
thickening of intramyocardial arterioles occur in one
third of the patients. Clinical impairment by
myocardial involvement, however, is less common.
177
Clinical Features of SS
Systemic sclerosis has a female-to-male ratio of 3 : 1, with a peak
incidence in the 50- to 60-year age group. Although systemic
sclerosis shares many features with SLE, rheumatoid arthritis
(Chapter 26), and polymyositis (Chapter 27), its distinctive
features are the striking cutaneous changes, notably skin
thickening
178
Raynaud phenomenon
manifested as episodic
vasoconstriction of the arteries and arterioles of the extremities,
is seen in virtually all patients and precedes other symptoms in
70% of cases.
179
Dysphagia
attributable to esophageal fibrosis and
its resultant hypomotility are present in more than 50% of
patients. Eventually, destruction of the esophageal wall leads to
atony and dilation, especially at its lower end
180
Respiratory difficulties caused by the pulmonary fibrosis may
result in
right-sided cardiac dysfunction, and myocardial fibrosis
may cause either arrhythmias or cardiac failure. Mild
proteinuria occurs in as many as 30% of patients, but rarely is
the proteinuria severe enough to cause a nephrotic syndrome
181
The most ominous manifestation is
malignant hypertension
(Chapter 11), with the subsequent development of fatal renal
failure, but in its absence progression of the disease may be
slow
182
The disease tends to be more severe in
blacks, especially
black women. As treatment of the renal crises has improved,
pulmonary disease has become the major cause of death in
systemic sclerosis
183
DNA topoisomerase I (anti-Scl 70), ANA type`
is highly specific. Depending
on the ethnic group and the assay, it is present in 10% to 20% of
patients with diffuse systemic sclerosis. Patients who have this
antibody are more likely to have pulmonary fibrosis and
peripheral vascular disease
184
anticentromere
| antibody
found in 20% to 30% of patients, who tend to have
the CREST syndrome. Patients with this syndrome have
relatively limited involvement of skin, often confined to fingers,
forearms, and face, and calcification of the subcutaneous
tissues
185
Inflammatory Myopathies
Inflammatory myopathies comprise an uncommon,
heterogeneous group of disorders characterized by injury and
inflammation of mainly the skeletal muscles, which are probably
immunologically mediated.
186
Inflammatory Myopathies common types
dermatomyositis, polymyositis, and inclusion-body myositis, are
included in this category. These may occur alone or with other
immune-mediated diseases, particularly systemic sclerosis
187
Mixed Connective Tissue Disease
The term mixed connective tissue disease is used to
describe a disease with clinical features that are a mixture
of the features of SLE, systemic sclerosis, and
polymyositis
188
Mixed Connective Tissue Disease is characterised by
characterized serologically by high
titers of antibodies to ribonucleoprotein particle-containing U1
ribonucleoprotein. Typically, mixed connective tissue disease
presents with synovitis of the fingers, Raynaud phenomenon and
mild myositis, but renal involvement is modest and there is a
good response to corticosteroids, at least in the short term.
189
Serious complications
| of mixed connective tissue disease include
pulmonary
| hypertension, interstitial lung disease, and renal disease
190
Polyarteritis Nodosa and Other
| Vasculitides
Polyarteritis nodosa belongs to a group of diseases characterized
by necrotizing inflammation of the walls of blood vessels and
showing strong evidence of an immunologic pathogenetic
mechanism
191
noninfectious vasculitis
differentiates these conditions from those due to direct infection
of the blood vessel wall (such as occurs in the wall of an
abscess) and serves to emphasize that any type of vessel may be
involved—arteries, arterioles, veins, or capillaries.
192
IgG4-Related Disease
gG4-related disease (IgG4-RD) is a newly recognized
constellation of disorders characterized by tissue infiltrates
dominated by IgG4 antibody-producing plasma cells and
lymphocytes, particularly T cells, storiform fibrosis, obliterative
phlebitis, and usually increased serum IgG4
193
Mikulicz syndrome
enlargement and
| fibrosis of salivary and lacrimal glands
