2732 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

self-antigen may lead to activation of autoreactive lymphocytes. One of

the best examples of autoreactivity and autoimmune disease resulting

from molecular mimicry is rheumatic fever, in which antibodies to

the M protein of streptococci cross-react with myosin, laminin, and

other matrix proteins as well as with neuronal antigens. Deposition of

these autoantibodies in the heart initiates an inflammatory response,

whereas their penetration into the brain can result in Sydenham’s chorea. Molecular mimicry between microbial proteins and host tissues

has been reported in type 1 diabetes mellitus, rheumatoid arthritis,

systemic lupus erythematosus (SLE), celiac disease, and multiple sclerosis. It is presumed that infectious agents may be able to overcome

self-tolerance because they possess pathogen-associated molecular

patterns (PAMPs). These molecules (e.g., bacterial endotoxin, RNA, or

DNA) exert adjuvant-like effects on the immune system by interacting

with Toll-like receptors (TLRs) and other pattern recognition receptors

(PRRs) that increase the immunogenicity and immunostimulatory

capacity of the microbial material. The adjuvants activate dendritic

cells, which in turn stimulate the activation of previously quiescent

lymphocytes that recognize both microbial antigens and self-antigens.

Alternatively, PAMPs can activate PRRs on tissue epithelial cells, which

then activate dendritic cells. Cellular and tissue damage can result in

release of damage-associated molecular patterns (DAMPs), including

DNA, RNA nucleosomes, and other tissue debris, which may activate

cells of the inflammatory and immune systems through engagement of

the same array of PRRs. This pathway may lead to autoimmune disease

in individuals who have impairments in mechanisms for clearance of

tissue debris.

Although previous work focused on the role of pathogenic microorganisms in triggering autoimmunity, more recent studies have focused

on the role of the microbiome, the collection of nonpathogenic microorganisms that reside on various body surfaces. It has become clear

that the interaction between specific constituents of these microbiota

and the immune system can shape the nature of the immune response

to either favor or discourage immune/inflammatory responses. Thus,

some genera within the microbiome may favor a nonresponsive state

dominated by regulatory T cells, whereas others may favor the development of T effector cells and a proinflammatory state. Gender bias

in autoimmune conditions may also be favored by differences in the

dominant organisms within the microbiome.

Endogenous derangements of the immune system also contribute to

the loss of immunologic tolerance to self-antigens and the development

of autoimmunity (Table 355-2). Some autoantigens reside in immunologically privileged sites, such as the brain or the anterior chamber of

the eye. These sites are characterized by the inability of engrafted tissue

to elicit immune responses. Immunologic privilege results from a number of events, including the limited entry of proteins from those sites

into lymphatics, the local production of immunosuppressive cytokines

such as transforming growth factor β, and the local expression of molecules (including Fas ligand and PD-1 ligand) that can induce apoptosis

or quiescence of activated T cells. Lymphoid cells remain in a state of

immunologic ignorance (neither activated nor anergized) with regard

to proteins expressed uniquely in immunologically privileged sites. If

the privileged site is damaged by trauma or inflammation or if T cells

are activated elsewhere, proteins expressed at this site can become

immunogenic and be the targets of immunologic assault. In multiple

sclerosis and sympathetic ophthalmia, for example, antigens uniquely

expressed in the brain and eye, respectively, become the target of activated T cells.

Alterations in antigen presentation may also contribute to autoimmunity. Peptide determinants (epitopes) of a self-antigen that are

not routinely presented to lymphocytes may be recognized as a result

of altered proteolytic processing of the molecule and the ensuing

presentation of novel peptides (cryptic epitopes). When B cells rather

than dendritic cells present self-antigen, they may also present cryptic

epitopes that can activate autoreactive T cells. These cryptic epitopes

will not previously have been available to affect the silencing of

autoreactive lymphocytes. Furthermore, once there is immunologic

recognition of one protein component of a multimolecular complex,

reactivity may be induced to other components of the complex after

TABLE 355-1 Mechanisms Preventing Autoimmunity

1. Sequestration of self-antigens

2. Generation and maintenance of tolerance

a. Central deletion of autoreactive lymphocytes

b. Peripheral anergy of autoreactive lymphocytes

c. Receptor replacement in autoreactive lymphocytes

3. Regulatory mechanisms

a. Regulatory T cells

b. Regulatory B cells

c. Regulatory mesenchymal cells

d. Regulatory cytokines

e. Idiotype network

TABLE 355-2 Mechanisms of Autoimmunity

I. Exogenous

A. Molecular mimicry

B. Superantigenic stimulation

C. Microbial and tissue damage–associated adjuvanticity

II. Endogenous

A. Altered antigen presentation

1. Loss of immunologic privilege

2. Presentation of novel or cryptic epitopes (epitope spreading)

3. Alteration of self-antigen

4. Enhanced function of antigen-presenting cells

a. Costimulatory molecule expression

b. Cytokine production

B. Increased T-cell help

1. Cytokine production

2. Costimulatory molecules

C. Increased B-cell function

1. B-cell activating factor

2. Costimulatory molecules

D. Apoptotic defects or defects in clearance of apoptotic material

E. Cytokine imbalance

F. Altered immunoregulation

procedures, that autoantigen-binding cells could be demonstrated easily in the circulation of normal individuals, and that self-limited autoimmune phenomena frequently developed after tissue damage from

infection or trauma. These observations indicated that clones of cells

capable of responding to autoantigens were present in the repertoire of

antigen-reactive cells in normal adults and suggested that mechanisms

in addition to clonal deletion were responsible for preventing their

activation.

Currently, three general processes are thought to be involved in the

maintenance ofselective unresponsivenessto autoantigens(Table 355-1):

(1) sequestration of self-antigens, rendering them inaccessible to the

immune system; (2) specific unresponsiveness (tolerance or anergy)

of relevant T or B cells; and (3) limitation of potential reactivity by

regulatory mechanisms. Derangements of these normal processes

may predispose to the development of autoimmunity (Table 355-2).

In general, induction of autoimmunity requires both an exogenous

trigger, such as bacterial or viral infection or cigarette smoking or

a perturbation of the microbiome, and the presence of endogenous abnormalities in the cells of the immune system. A number

of exogenous triggers have been identified. For example, microbial

superantigens, such as staphylococcal protein A and staphylococcal

enterotoxins, are substances that can stimulate a broad range of T and

B cells through specific interactions with selected families of immune

receptors, irrespective of their antigen specificity. If autoantigenreactive T and/or B cells express these receptors, autoimmunity may

be induced by stimulation with these substances. Alternatively, molecular mimicry or cross-reactivity between a microbial product and a

Autoimmunity and Autoimmune Diseases

2733CHAPTER 355

internalization and presentation of all molecules within the complex

(epitope spreading). Finally, inflammation, environmental agents,

drug exposure, or normal senescence may cause a posttranslational

alteration in proteins, resulting in the generation of immune responses

that cross-react with normal self-proteins. For example, the induction

and/or release of protein arginine deiminase enzymes results in the

conversion of arginine residues to citrullines in a variety of proteins,

thereby altering their capacity to induce immune responses. Production

of antibodies to citrullinated proteins has been observed in rheumatoid arthritis and chronic lung disease as well as in normal smokers.

These antibodies can contribute to organ pathology. Alterations in

the availability and presentation of autoantigens may be important

components of immunoreactivity in certain models of organ-specific

autoimmune diseases. In addition, these factors may be relevant to an

understanding of the pathogenesis of various drug-induced autoimmune conditions. However, the diversity of autoreactivity manifesting

in non-organ-specific systemic autoimmune diseasessuggeststhat these

conditions may result from a more general activation of the immune

system rather than from an alteration in individual self-antigens.

Many autoimmune diseases are characterized by the presence of

antibodies that react with antigens present in apoptotic material.

Defects in the clearance of apoptotic material have been shown to

elicit autoimmunity and autoimmune disease in a number of animal

models. Moreover, such defects have been found in patients with SLE.

Apoptotic debris that is not cleared quickly by the immune system can

function as endogenous ligands for a number of PRRs on dendritic

cells and B cells. Under such circumstances, dendritic cells and/or

B cells are activated, and an immune response to apoptotic debris can

develop. In addition, the presence of uncleared extracellular apoptotic

material within germinal centers of secondary lymphoid organs in

patients with SLE may facilitate the direct activation of autoimmune

B-cell clones. Similarly, cellular contents, including nuclear material,

released from neutrophils undergoing a form of cell death referred to

as NETosis, may be particularly immunogenic.

Deficiency in C1q, likewise, can predispose or exacerbate autoimmunity. C1q assists in the clearance of apoptotic debris and NETotic

material binding to IgM autoantibodies and to inhibitory receptors on

monocytes and dendritic cells. If C1q is not present, a mechanism of

immune suppression is lost. Moreover, if antibodies have undergone

class switch recombination to IgG, the apoptotic debris containing

immune complexes will engage activating Fc receptors on myeloid

cells to induce an inflammatory response. Studies in a number of

experimental models have suggested that intense stimulation of T

lymphocytes can produce nonspecific signals that directly lead to

polyclonal B-cell activation with the formation of multiple autoantibodies and bypass the need for antigen-specific helper T cells. For

example, antinuclear, antierythrocyte, and antilymphocyte antibodies

are produced during the chronic graft-versus-host reaction. In addition, autoimmune hemolytic anemia and immune complex–mediated

glomerulonephritis can be induced in this manner. Direct stimulation

of B lymphocytes can also lead to the production of autoantibodies.

Thus, the administration of polyclonal B-cell activators, such as bacterial endotoxin, to normal mice leads to the production of a number of

autoantibodies, including those to DNA and IgG (rheumatoid factor).

A variety of genetic modifications resulting in hyperresponsiveness

of B cells also can lead to the production of autoantibodies and, in

animals of appropriate genetic background, a lupus-like syndrome.

Moreover, excess B-cell activating factor (BAFF), a B-cell survival-promoting cytokine, can impair B-cell tolerance, cause T cell–independent

B-cell activation, and lead to the development of autoimmunity. SLE

can also be induced in mice through exuberant dendritic cell activation, through a redundancy of TLR7 and transposition to the Y chromosome (as in BXSB-Yaa mice), or through exposure to CpG, a ligand

for TLR9. The ensuing induction of inflammatory mediators can cause

a switch from the production of nonpathogenic IgM autoantibodies

to the production of pathogenic IgG autoantibodies in the absence of

antigen-specific T-cell help. Aberrant selection of the B- or T-cell repertoire at the time of antigen receptor expression can also predispose

to autoimmunity. For example, B-cell immunodeficiency caused by

an absence of the B-cell receptor–associated kinase (Bruton’s tyrosine

kinase) leads to X-linked agammaglobulinemia. This syndrome is

characterized by reduced B-cell numbers. This leads to high levels

of BAFF, which alter B-cell selection and result in greater survival of

autoreactive B cells. Likewise, negative selection of autoreactive T cells

in the thymus requires expression of the autoimmune regulator (AIRE)

gene that enables the expression of tissue-specific proteins in thymic

medullary epithelial cells. Peptides from these proteins are expressed

in the context of major histocompatibility complex (MHC) molecules

and mediate the central deletion of autoreactive T cells. The absence

of AIRE gene expression leads to a failure of negative selection of

autoreactive cells, autoantibody production, and severe inflammatory

destruction of multiple organs. Individuals deficient in AIRE gene

expression develop autoimmune polyendocrinopathy–candidiasis–

ectodermal dystrophy (APECED).

Primary alterations in the activity of T and/or B cells, cytokine

imbalances, or defective immunoregulatory circuits may also contribute

to the emergence of autoimmunity. Diminished production of tumor

necrosis factor (TNF) and interleukin (IL) 10 has been reported to be

associated with the development of autoimmunity. Overproduction or

therapeutic administration of type 1 interferon has also been associated

with autoimmunity. Overexpression of costimulatory molecules on

T cells similarly can lead to autoantibody production.

Autoimmunity may also result from an abnormality of immunoregulatory mechanisms. Observations made in both human autoimmune

disease and animal models suggest that defects in the generation

and expression of regulatory T-cell (Treg) activity may allow the

production of autoimmunity. It has been appreciated that the IPEX

(immunodysregulation, polyendocrinopathy, enteropathy X-linked)

syndrome results from the failure to express the FOXP3 gene, which

encodes a molecule critical in the differentiation of Tregs. Administration of normal Tregs or of factors derived from them can prevent the

development of autoimmune disease in rodent models of autoimmunity, and allogeneic stem cell transplantation ameliorates human IPEX.

Abnormalities in the function of Tregs have been noted in a number

of human autoimmune diseases, including rheumatoid arthritis and

SLE, although it remains uncertain whether these functional abnormalities are causative or are secondary to inflammation. One of the

mechanisms by which Tregs control immune/inflammatory responses

is by the production of the cytokine IL-10. In this regard, children with

a deficiency in the expression of IL-10 or the IL-10 receptor develop

inflammatory bowel disease that mimics Crohn’s disease and that can

be cured by allogeneic stem cell transplantation. Furthermore, recent

data indicate that B cells may also exert regulatory function, largely

through the production of IL-10. Deficiency of IL-10-producing regulatory B cells can prolong the course of multiple sclerosis in an animal

model, and such cells are thought to be functionally diminished in

human SLE. Finally, myeloid cells can inhibit immune responses.

Depending on the microenvironment and cytokine stimulation, macrophages can functionally differentiate into classical M1 or inflammatory macrophages with enhanced microbicidal and cytotoxic activities

or alternatively activated or M2 macrophages with anti-inflammatory

and reparative capabilities. Abnormalities in this balance have been

noted to contribute to animal models of autoimmunity and to human

disease where a switch from M2-like to M1-like macrophages seems to

be involved in development of disease activity in SLE. Importantly, C1q

helps maintain macrophages in a quiescent state. Of note, dendritic

cells also begin as tolerogenic cells but become immunogenic with activation. This pathway to autoimmunity has become important with the

widespread use of checkpoint inhibitor therapy for cancer, which leads

to autoimmune symptoms in up to one-third of recipients.

It should be apparent that no single mechanism can explain all

the varied manifestations of autoimmunity or autoimmune disease.

Furthermore, genetic evaluation has shown that convergence of a

number of abnormalities is most often required for the induction of

an autoimmune disease. Additional factors that appear to be important

determinants in the induction of autoimmunity include age, sex (many

autoimmune diseases are far more common in women), exposure to

infectious agents, and environmental contacts. How these disparate

2734 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

factors affect the capacity to develop self-reactivity is currently being

investigated intensively.

■ GENETIC CONSIDERATIONS

Evidence in humans that there are susceptibility genes for autoimmunity comes from family studies and especially from studies of

twins. Studies in type 1 diabetes mellitus, rheumatoid arthritis,

multiple sclerosis, and SLE have shown ~15–30% disease concordance

in monozygotic twins, whereas the figure is <5% for dizygotic twins.

The occurrence of different autoimmune diseases within the same

family has suggested that certain susceptibility genes may predispose to

a variety of autoimmune diseases. Many hundreds of genetic polymorphisms associated with one or more autoimmune diseases have been

identified to date. As predicted, some genes are associated with multiple autoimmune diseases, whereas others are specifically associated

with only one autoimmune condition. Moreover, recent genetic evidence suggests that clusters of genetic risk factors can commonly be

found in groups of autoimmune diseases. For example, one group of

genetic risk factors is most frequently associated with Crohn’s disease,

psoriasis, and multiple sclerosis, whereas a second is most strongly

associated with celiac disease, rheumatoid arthritis, and SLE. These

results imply that autoimmune diseases with widely different clinical

presentations and patterns of organ involvement may involve similar

immunopathogenic pathways or endophenotypes. For example, the

same allele of the gene encoding PTPN22 is associated with multiple

autoimmune diseases. Its product is a phosphatase expressed by a variety of hematopoietic cells that downregulates antigen receptor–

mediated stimulation of T and B cells. The risk allele is associated with

type 1 diabetes mellitus, rheumatoid arthritis, and SLE in some populations. In recent years, genome-wide association studies have demonstrated a variety of other genes that are involved in human autoimmune

diseases. Importantly, the genetic contribution to autoimmune disease

differs somewhat in people of different ancestries. Most genes individually confer a relatively low risk for autoimmune diseases and are

found in normal individuals but, in aggregate, are associated with

substantial risk of disease. In addition, most polymorphisms associated

with autoimmune diseases are in noncoding regions of DNA, implying

that protein expression levels rather that altered function might convey

most genetic risk for autoimmune diseases. Abnormalities in epigenetics or the mechanisms, such as cellular metabolism, controlling and

influencing gene expression have also been implicated in contributing

to autoimmune diseases. No single gene or epigenetic modification has

been identified that is essential for autoimmune diseases. In addition to

this evidence from humans, certain inbred mouse strains reproducibly

develop specific spontaneous or experimentally induced autoimmune

diseases, whereas others do not. These findings have now led to a

search for genes that might be protective.

The strongest consistent association for susceptibility to autoimmune disease is with particular MHC alleles. It has been suggested that

the association of MHC genotype with autoimmune disease relates to

differences in the ability of different allelic variations of MHC molecules to present autoantigenic peptides to autoreactive T cells. An alternative hypothesis involves the role of MHC alleles in shaping the T-cell

receptor repertoire during T-cell ontogeny in the thymus. In addition,

specific MHC gene products may themselves be the source of peptides

that can be recognized by T cells. Cross-reactivity between such MHC

peptides and peptides derived from proteins produced by common

microbes may trigger autoimmunity by molecular mimicry. Finally,

there appears to be a contribution from non-MHC genes encoded

within the MHC locus. However, MHC genotype alone does not determine the development of autoimmunity. Identical twins are far more

likely to develop the same autoimmune disease than MHC-identical

nontwin siblings. Studies of the genetics of type 1 diabetes mellitus,

SLE, rheumatoid arthritis, and multiple sclerosis in humans and mice

have identified several independently segregating disease susceptibility

loci in addition to the MHC. Genes that encode molecules of the innate

immune response are also involved in autoimmunity. In humans,

inherited homozygous deficiency of the early proteins of the classic

pathway of complement (C1q, C4, or C2) as well as genes involved

in the type 1 interferon pathway are very strongly associated with the

development of SLE.

■ IMMUNOPATHOGENIC MECHANISMS IN

AUTOIMMUNE DISEASES

The mechanisms of tissue injury in autoimmune diseases can be

divided into antibody-mediated and cell-mediated processes. Representative examples are listed in Table 355-3.

The pathogenicity of autoantibodies can be mediated through several mechanisms, including opsonization of soluble factors or cells,

activation of an inflammatory cascade via the complement system, and

interference with the physiologic function of soluble molecules or cells

or immune complex–mediated activation of cells through engagement

of activating Fc receptors.

In autoimmune thrombocytopenic purpura, opsonization of platelets targets them for elimination by phagocytes. Likewise, in autoimmune hemolytic anemia, binding of immunoglobulin to red cell

membranes leads to phagocytosis and lysis of the opsonized cell. Goodpasture’s syndrome, a disease characterized by lung hemorrhage and

TABLE 355-3 Mechanisms of Tissue Damage in Autoimmune Disease

EFFECTOR MECHANISM TARGET DISEASE

Autoantibody Blocking or inactivation α Chain of the nicotinic acetylcholine

receptor

Myasthenia gravis

Phospholipid–β2

-glycoprotein I complex Antiphospholipid syndrome

Insulin receptor Insulin-resistant diabetes mellitus

Intrinsic factor Pernicious anemia

Stimulation TSH receptor (LATS) Graves’ disease

Proteinase-3 (ANCA) Granulomatosis with polyangiitis

Epidermal cadherin Pemphigus vulgaris

Desmoglein 3

Complement activation α3

 Chain of collagen IV Goodpasture’s syndrome

Immune complex formation Double-stranded DNA Systemic lupus erythematosus

Immunoglobulin Rheumatoid arthritis

Opsonization Platelet GpIIb:IIIa Autoimmune thrombocytopenic purpura

Rh antigens, I antigen Autoimmune hemolytic anemia

Antibody-dependent cellular cytotoxicity Thyroid peroxidase, thyroglobulin Hashimoto’s thyroiditis

T cells Cytokine production Rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus

Cellular cytotoxicity Type 1 diabetes mellitus

Abbreviations: ANCA, antineutrophil cytoplasmic antibody; LATS, long-acting thyroid stimulator; TSH, thyroid-stimulating hormone.

Autoimmunity and Autoimmune Diseases

2735CHAPTER 355

severe glomerulonephritis, represents an example of antibody binding

leading to local activation of complement and neutrophil accumulation

and activation. The autoantibody in this disease binds to the α3 chain

of type IV collagen in the basement membrane. In SLE, activation of

the complement cascade at sites of immunoglobulin deposition in renal

glomeruli is considered to be a major mechanism of renal damage.

Moreover, the DNA- and RNA-containing immune complexes in SLE

activate TLR9 and TLR7, respectively, in plasmacytoid dendritic cells

and promote the production of type 1 interferon and proinflammatory

cytokines conducive to amplification of the autoimmune response.

Autoantibodies can also interfere with normal physiologic functions of

cells or soluble factors. Autoantibodies to hormone receptors can lead to

stimulation of cells or to inhibition of cell function through interference

with receptor signaling. For example, long-acting thyroid stimulators—

autoantibodies that bind to the receptor for thyroid-stimulating hormone

(TSH)—are present in Graves’ disease and function as agonists, causing

the thyroid to respond as if there were an excess of TSH. Alternatively,

antibodies to the insulin receptor can cause insulin-resistant diabetes

mellitusthrough receptor blockade. In myasthenia gravis, autoantibodies

to the acetylcholine receptor can be detected in 85–90% of patients and

are responsible for muscle weakness. The exact location of the antigenic

epitope, the valence and affinity of the antibody, and perhaps other

characteristics determine whether activation or blockade results from

antibody binding.

Antiphospholipid antibodies are associated with thromboembolic

events in primary and secondary antiphospholipid syndrome and have

also been associated with fetal loss. The major antibody is directed

to the phospholipid–β2

-glycoprotein I complex and appears to exert

a procoagulant effect. In pemphigus vulgaris, autoantibodies bind to

desmoglein 1 and 3, components of the epidermal cell desmosome,

and play a role in the induction of the disease. These antibodies

exert their pathologic effect by disrupting cell–cell junctions through

stimulation of the production of epithelial proteases, with consequent

blister formation. Cytoplasmic antineutrophil cytoplasmic antibody

(c-ANCA), found in granulomatosis with polyangiitis, is an antibody

to an intracellular antigen, the 29-kDa serine protease (proteinase-3).

In vitro experiments have shown that IgG anti-c-ANCA causes cellular

activation and degranulation of primed neutrophils.

It is important to note that autoantibodies of a given specificity

may cause disease only in genetically susceptible hosts, as has been

shown in experimental models of myasthenia gravis, SLE, rheumatic

fever, and rheumatoid arthritis. Furthermore, once organ damage is

initiated, new inflammatory cascades are initiated that can sustain and

amplify the autoimmune process. Finally, some autoantibodies seem to

be markers for disease but have, as yet, no known pathogenic potential.

In many autoimmune diseases, myeloid cells play an essential role

as effector cells of inflammation. M1-like macrophages activated by

cytokines, such as type 2 interferon, immune complexes through

activating Fc receptors, or surface or intracellular TLRs can produce a

number of inflammatory cytokines, including IL-1, TNF, and IL-6, that

contribute to tissue inflammation.

■ AUTOIMMUNE DISEASES

Manifestations of autoimmunity are found in a large number of pathologic conditions. However, their presence does not necessarily imply

that the pathologic process is an autoimmune disease. A number of

attempts to establish formal criteria for the classification of diseases as

autoimmune have been made, but none is universally accepted. One

set of criteria is shown in Table 355-4; however, this scheme should be

viewed merely as a guide in consideration of the problem.

To classify a disease as autoimmune, it is necessary to demonstrate

that the immune response to a self-antigen causes the observed pathology. Initially, the detection of antibodies to the affected tissue in the

serum of patients suffering from various diseases was taken as evidence

that these diseases had an autoimmune basis. However, such autoantibodies can also be found when tissue damage is caused by trauma

or infection and, in these cases, are secondary to tissue damage. Thus,

autoimmunity must be shown to be pathogenic before a disease is categorized as autoimmune.

To confirm autoantibody pathogenicity, it may be possible to transfer disease to experimental animals by the administration of autoantibodies from a patient leading to the development of pathology in the

recipient that is similar to that seen in the patient. This scenario has

been documented, for example, in Graves’ disease. Some autoimmune

diseases can be transferred from mother to fetus and are observed in

the newborn babies. The symptoms of the disease in the newborn

usually disappear as the levels of maternal antibody decrease. An

exception, however, is congenital heart block, in which damage to the

developing conducting system of the heart follows in utero transfer of

anti-Ro antibody from the mother to the fetus. This antibody transfer

can result in a permanent developmental defect in the heart.

In most situations, the critical factors that determine when the

development of autoimmunity results in autoimmune disease have not

been delineated. The relationship of autoimmunity to the development

of autoimmune disease may be associated with the fine specificity of

the antibodies and their isotype or T cells or their specific effector

capabilities. In many circumstances, a mechanistic understanding of

the pathogenic potential of autoantibodies has not been established. In

some autoimmune diseases, biased production of cytokines by helper

T (TH) cells may play a role in pathogenesis. In this regard, T cells can

differentiate into specialized effector cells that predominantly produce

interferon γ (TH1), IL-4 (TH2), or IL-17 (TH17) or that provide help to

B cells (T follicular helper [Tfh]) (Chap. 349). TH1 cells facilitate macrophage activation and classic cell-mediated immunity, whereas TH2

cells are thought to have regulatory functions and are involved in the

resolution of normal immune responses as well as in the development

of responses to a variety of parasites. TH17 cells produce a number of

inflammatory cytokines, including IL-17 and IL-22, and seem to be

prominently involved in host resistance to certain fungal infections.

Tfh cells help B cells by constitutively producing IL-21. In a number of

autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis,

type 1 diabetes mellitus, ankylosing spondylitis, and Crohn’s disease,

there appears to be biased differentiation of TH1 and TH17 cells, with

resultant organ damage. Studies suggest an accentuated differentiation

of TH17 cells associated with animal models of inflammatory arthritis,

whereas increased differentiation of Tfh cells has been associated with

SLE. Importantly, genetically determined or environmentally induced

features of the target organ may determine susceptibility of the target

organ to autoantibodies or autoreactive T cell–mediated damage.

■ ORGAN-SPECIFIC VERSUS SYSTEMIC

AUTOIMMUNE DISEASES

The spectrum of autoimmune diseases ranges from conditions specifically affecting a single organ to systemic disorders that involve

many organs (Table 355-5). Hashimoto’s autoimmune thyroiditis is

an example of an organ-specific autoimmune disease (Chap. 382). In

this disorder, a specific lesion in the thyroid is associated with infiltration of mononuclear cells and damage to follicular cells. Antibody

to thyroid constituents can be demonstrated in nearly all cases. Other

TABLE 355-4 Human Autoimmune Disease: Presumptive Evidence for

Immunologic Pathogenesis

Major Criteria

1. Presence of autoantibodies or evidence of cellular reactivity to self

2. Documentation of relevant autoantibody or lymphocytic infiltrate in the

pathologic lesion

3. Demonstration that relevant autoantibody or T cells can cause tissue

pathology

a. Transplacental transmission

b. Adaptive transfer into animals

c. In vitro impact on cellular function

Supportive Evidence

1. Reasonable animal model

2. Beneficial effect from immunosuppressive agents

3. Association with other evidence of autoimmunity

4. No evidence of infection or other obvious cause

2736 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 355-5 Diseases on the Autoimmune Spectrum

Organ Specific

Graves’ disease Vitiligo

Hashimoto’s thyroiditis Autoimmune hemolytic anemia

Autoimmune polyglandular syndrome Autoimmune thrombocytopenic

purpura

Type 1 diabetes mellitus Pernicious anemia

Insulin-resistant diabetes mellitus Myasthenia gravis

Immune-mediated infertility Multiple sclerosis

Autoimmune Addison’s disease Guillain-Barré syndrome

Pemphigus vulgaris Stiff-man syndrome

Pemphigus foliaceus Acute rheumatic fever

Dermatitis herpetiformis Sympathetic ophthalmia

Autoimmune alopecia Goodpasture’s syndrome

Primary biliary cirrhosis

Organ Nonspecific (Systemic)

Systemic lupus erythematosus Granulomatosis with polyangiitis

Rheumatoid arthritis Antiphospholipid syndrome

Systemic necrotizing vasculitis Sjögren’s syndrome

organ- or tissue-specific autoimmune disorders include pemphigus

vulgaris, autoimmune hemolytic anemia, idiopathic thrombocytopenic

purpura, Goodpasture’s syndrome, myasthenia gravis, and sympathetic

ophthalmia. One important feature of some organ-specific autoimmune diseases is the tendency for overlap, such that an individual

with one specific syndrome is more likely to develop a second syndrome. For example, there is a high incidence of pernicious anemia

in individuals with autoimmune thyroiditis. More striking is the

tendency for individuals with an organ-specific autoimmune disease

to develop multiple other manifestations of autoimmunity without the

development of associated organ pathology. Thus, as many as 50% of

individuals with pernicious anemia have non-cross-reacting antibodies

to thyroid constituents, whereas patients with myasthenia gravis may

develop antinuclear antibodies, antithyroid antibodies, rheumatoid

factor, antilymphocyte antibodies, and polyclonal hypergammaglobulinemia. Part of the explanation may relate to the genetic elements

shared by individuals with these different diseases.

Systemic autoimmune diseases differ from organ-specific diseases in

that pathologic lesions are found in multiple diverse organs and tissues.

The hallmark of these conditions is the demonstration of associated

relevant autoimmune manifestations that are likely to have an etiologic

role in organ pathology. SLE represents the prototype of these disorders

because of its abundant autoimmune manifestations that characteristically involve the kidneys, joints, skin, serosal surfaces, blood vessels,

and central nervous system (Chap. 356). The disease is associated with

a vast array of autoantibodies whose production appears to be a part

of a generalized hyperreactivity of the humoral immune system. Other

features of SLE include generalized B-cell hyperresponsiveness and

polyclonal hypergammaglobulinemia. Current evidence suggests that

both hypo- and hyperresponsiveness to antigen can lead to survival

and activation of autoreactive B cells in SLE. The autoantibodies in SLE

are thought to arise as part of an accentuated T cell–dependent B-cell

response since most pathogenic anti-DNA autoantibodies exhibit evidence of extensive somatic hypermutation.

TREATMENT

Autoimmune Diseases

Treatment of autoimmune diseases can focus on suppressing the

induction of autoimmunity, restoring normal regulatory mechanisms, or inhibiting the effector mechanisms. To decrease the

number or function of autoreactive cells, immunosuppressive or

ablative therapies are most commonly used. In recent years, cytokine blockade has been demonstrated to be effective in preventing

immune activation in some diseases or in inhibiting the extensive

inflammatory effector mechanisms characteristic of these diseases.

New therapies have also been developed to target lymphoid cells

more specifically by blocking a costimulatory signal needed for

T- or B-cell activation, by blocking the migratory capacity of

lymphocytes, or by eliminating the effector T cells or B cells. The

efficacy of these therapies in some diseases—e.g., SLE (belimumab),

rheumatoid arthritis (TNF neutralization, IL-6 receptor blockade,

CD28 competition, B-cell depletion, IL-1 neutralization), psoriasis (IL-12/23 depletion, TNF neutralization), and inflammatory

bowel disease (TNF neutralization, IL-12/23 neutralization)—has

been demonstrated. Small molecules that block cytokine signaling

pathways by blocking the Janus kinase (JAK) family of kinases have

also entered the clinic. Biologicals that delete B cells have demonstrated efficacy in a number of autoimmune diseases characterized

by pathogenic effector T cells, highlighting the importance of

B cells as antigen-presenting cells. Finally, there is renewed interest

in cellular therapies in autoimmune diseases, including hematopoietic stem cell reconstitutions and treatment with immunosuppressive mesenchymal stem cells. Therapies that prevent target organ

damage or support target organ function also remain important in

the management of autoimmune disease.

■ FURTHER READING

Caielli S et al: Oxidized mitochondrial nucleoids release by neutrophils drive type I interferon production in human lupus. J Exp

Med 5:697, 2016.

Jackson SW et al: B cells take the front seat: Dysregulated B cell signals

orchestrate loss of tolerance and autoantibody production. Curr Opin

Immunol 33:70, 2015.

Teruel M, Alacron-Riquelme ME: Genetics of systemic lupus

erythematosus and Sjögren’s syndrome: An update. Curr Opin Rheumatol 28:506, 2016.

Tsokos GC et al: New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 22:716, 2016.

Ueno H: T follicular helper cells in human autoimmunity. Curr Opin

Immunol 43:24, 2016.

Yin Y et al: Normalization of CD4+ T cell metabolism reverses lupus.

Science Transl Med 7:274, 2015.

DEFINITION AND PREVALENCE

Systemic lupus erythematosus(SLE) is an autoimmune disease in which

organs and cells undergo damage initially mediated by tissue-binding

autoantibodies and immune complexes. In most patients, autoantibodies are present for a few years before the first clinical symptom appears.

Ninety percent of patients are women of child-bearing years; people of

all genders, ages, and ethnic groups are susceptible. The prevalence of

SLE in the United States is 81–144 per 100,000. Prevalence is higher

in all nonwhite races/ethnicities compared to whites, with the highest

prevalence in African-American and Afro-Caribbean women and the

lowest in white men. SLE is 5.5–6.5 times more prevalent in women

than in men.

PATHOGENESIS AND ETIOLOGY

The proposed pathogenic mechanisms of SLE are illustrated in

Fig. 356-1. The abnormal immune responses underlying SLE may

be summarized as leading to production of increased quantities and

356 Systemic Lupus

Erythematosus

Bevra Hannahs Hahn, Maureen McMahon

Systemic Lupus Erythematosus

2737CHAPTER 356

of autoantibody-secreting cells. Both subsets have abnormal epigenetic

modifications with more open chromatin than normal B cells and

thus are subject to hyperactivation via their B-cell receptors, Toll-like

receptor 7 (TLR7), and cytokines such as IL-21. Therefore, SLE B cells

are poised to react to their environment with increased autoantibody

secretion. Central B cells (germinal center, follicular B cells) also

produce autoantibodies. DN2 and isotype-switched memory B cells

differentiate into both short-lived (in periphery) and long-lived (in

bone marrow) plasma cells that secrete autoantibodies and are elevated

in patients with active SLE. B cells not only present antigens, but they

also secrete IL-6 and IL-10, which promote autoreactive B-cell survival

(as does estrogen). Some B and T lymphocyte subsets have altered

metabolism (abnormal mitochondrial electron transport, membrane

potential, and oxidative stress), increased glucose utilization, increased

pyruvate production, activation of mechanistic target of rapamycin

(mTOR), and increased autophagy. Helper T cells are easily activated

and driven into either differentiation, activation, or apoptosis. In SLE

patients, after peptides bind the T-cell receptor (TCR), T-cell signaling

is abnormal, beginning with complexing of TCR with the common

chain FcRγ rather than the usual CD3ζ. This results in abnormal elevations of phosphorylated Syk, the P13K/mTORC pathway, CaMKIV,

PP2A, and calcineurin, with resultant increased calcium influx. Rhoassociated protein kinases (ROCK) pathways are also elevated, probably via cytokine receptors, with increases in STAT3 and therefore in

IL-17. The net result is underproduction of IL-2 (needed for survival of

T lymphocytes and for generation of regulatory T cells) and elevation

GENES

High hazard ratios (≥6);

Deficiencies of C1q,C2,C4 (rare)

TREX1 mutations affecting DNA

 degradation (rare)

Affecting Ag presentation or persistence,

 e.g., phagocytosis of immune complexes

 HLA-DRB1 (*1501,*0301), DR3, DQA2

 CR2, FCGR2A/B

Enhance innate immunity, including production of IFNs

 TNFAIP3, IRF5/TNPO3, IRF7/PHRF1, ITGAM, ICAMs

Alter adaptive immunity B and/or T cell signaling

 BANK1, STAT4, MSHS, IZKF3, TCF7

GENES FOR LUPUS NEPHRITIS

HLA-DR3, STAT4, APOL1 (African Americans),

FCGR3A, ITGAM, IRF5, IRF7, TNFSF4 (Ox40L), DNAse1

ENVIRONMENT/MICROENVIRONMENT

 Ultraviolet light, smoking, crystalline

 silica, ?EBV infection,

 femaleness

EPIGENETICS

Hypomethylation of DNA: In CD4+T, B and monocytes

 Some affect IFN production

 Histone modifications: Some increase expression

 of predisposing genes and/or IFN production

 MicroRNA affecting gene expression

 Mir-21, -146A, -155, -569, -30A, Let-7a

PREDISPOSING FACTORS

Defective

suppressive

networks

Ag

DC

C3

C3a

Rash

Nephritis

Arthritis

Leukopenia

CNS dz

Carditis

Clotting

Etc.

Renal failure

Artherosclerosis

Pulm fibrosis

Stroke

Damage from Rx

Etc.

Chr. inflam.

Chr. oxid.

2. Abnormal

Immune Response

3. Autoantibodies

Immune Complexes

4. Inflammation 5. Damage

T cell

B cell

FIGURE 356-1 Pathogenesis of systemic lupus erythematosus (SLE). Pathogenesis is related in large part to production of increased quantities and immunogenic forms of

nucleic acids and other self-antigens, which drive autoimmune-inducing activation of innate immunity, autoantibodies, and T cells. Interactions between genes, environment,

and epigenetic changes drive increased autophagy, antigen (Ag) presentation, neutrophil NETosis, autoantibody formation with increased plasma cells, and production

of pathogenic effector T cells in TH1, TH17, and Tfh subsets, and in B-cell subsets with ineffective regulatory networks. Genes confirmed in more than one genome-wide

association analysis in multiple racial groups that increase susceptibility to SLE or lupus nephritis (HR ≥1.5) are listed (reviewed in Deng Y, Tsao B: Genetics of Human SLE,

in Dubois Lupus Erythematosus and Related Syndromes, 9th ed. DJ Wallace, BH Hahn [eds]. Philadelphia, Elsevier, 2019, pp 54-69; and Teruel M, Alarcon-Riquelme ME: The

genetic basis of systemic lupus erythematosus: What are the risk factors and what have we learned. J Autoimmun 74:161, 2016. Epigenetics are reviewed in Richardson

B: The interaction between environmental triggers and epigenetics in autoimmunity. Clin Immunol 192:1, 2018; and Scharer CD et al: Epigenetic programming underpins B cell

dysfunction in human SLE. Nat Immunol 20:1071, 2019. Environmental triggers are reviewed in Gulati G, Brunner HI: Environmental triggers in systemic lupus erythematosus.

Semin Arthritis Rheum 47:710, 2018). These result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes that deposit in tissue,

activate complement, induce cytokine and chemokine release causing inflammation, and over time lead to irreversible organ damage (reviewed in Arazi A et al: The

immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol 20:902, 2019; and Hahn BH: Pathogenesis of SLE, in Dubois Lupus Erythematosus and Related

Syndromes, 9th ed. DJ Wallace, BH Hahn [eds]. Philadelphia, Elsevier, 2019; and Anders HJ, Rovin B: A pathophysiology-based approach to diagnosis and treatment of

lupus nephritis. Kidney Intl 90:493, 2016). C1q, complement system; C3, complement component; CNS, central nervous system; DC, dendritic cell; EBV, Epstein-Barr virus;

HLA, human leukocyte antigen; FcR, immunoglobulin Fc-binding receptor; IL, interleukin; MCP, monocyte chemotactic protein; PTPN, phosphotyrosine phosphatase; UV,

ultraviolet.

immunogenic forms of nucleic acids, their accompanying proteins,

and other self-antigens, with resultant stimulation of large quantities

of autoantibodies. Autoantibodies of SLE are described in Fig. 356-1

and Table 356-1.

SLE autoimmunity may begin with activation of innate immunity, partly through binding of DNA, RNA, and proteins by Toll-like

receptors in plasmacytoid dendritic cells (pDCs) and monocytes/

macrophages. The pDCs (and other cells) produce interferon (IFN) α.

Upregulation of genes induced by IFNs (particularly IFN-α) is a genetic

“signature” in whole blood, peripheral blood cells, skin lesions, synovium, and kidneys in 50–80% of SLE patients and is particularly associated with active disease. Activated macrophages produce inflammatory

cytokines/chemokines such as interleukin (IL) 12, tumor necrosis

factor α (TNF-α), and the B-cell maturation/survival factor BLys/BAFF.

Furthermore, lupus phagocytic cells have reduced capacity to clear

immune complexes, apoptotic cells, and their autoantigen-containing

(e.g., DNA/RNA/Ro/La and phospholipid) surface blebs. The result

is persistence of large quantities of autoantigens. Neutrophils release

immunogenic DNA/protein-containing neutrophil extracellular traps

(NETs), and natural killer (NK) cells have reduced ability to kill autoreactive T and B cells or to produce the transforming growth factor β

(TGF-β) needed for development of regulatory T cells.

The activated innate immune system interacts with various subsets

of the B and T cells of adaptive immunity. SLE peripheral B cells have

increased numbers of naïve activated B cells and double-negative

B cells (DN2: CD27–CD11c+T-BET+CXCR5–), which are precursors

2738 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

of IL-17. These changes push the adaptive immune system toward

generation of helper T cells (TH1, Tfh, TH17) and away from downregulating regulatory T cells. Several of these B- and T-cell pathways are

targets of therapeutic interventions in current clinical trials.

Tissue damage begins with deposition of autoantibodies and/or

immune complexes, followed by destruction mediated by complement

activation and release of cytokines/chemokines. Nonimmune tissuefixed cells also are activated with resultant inflammation and damage,

such as basal cells of the dermis, synovial fibroblasts, renal mesangial

cells, podocytes and tubular epithelium, and endothelial cells throughout the body. Meanwhile, the initial immune attack is attracting into

the target tissues additional B and T cells, monocytes/macrophages,

dendritic cells, and plasma cells. Inflammation also causes release of

vasoactive peptides, oxidative damage, and release of growth factors

and fibrosing factors. Sclerosis/fibrosis with irreversible tissue damage

can occur in multiple tissues including kidneys, lungs, blood vessels,

and skin. Each of these processes depends on the individual’s genetic

background, environmental influences, and epigenetics.

SLE is usually a multigenic disease. Rare single-gene defects confer

high hazard ratios (HRs) for SLE (HR 5–25), including homozygous

deficiencies of early components of complement (C1q,r,s; C2; C4) and

a mutation in TREX1 (encoding a DNAase) on the X chromosome.

In most genetically susceptible individuals, normal alleles, mutations,

and/or copy numbers of multiple ancestral genes each contribute a

small amount to abnormal immune/inflammation/tissue damage

responses; if enough predisposing variations are present, disease

results. Approximately 90 genes with normal single nucleotide polymorphisms (SNPs; or mutations or altered copy numbers) increase

risk for SLE and/or clinical subsets of SLE and/or irreversible organ

damage. They have been identified in recent genome-wide or immunochip association studies in different ancestries. Individually, they

confer an HR for SLE of 1.4–3 and, even in combination, account

for only 28% of disease susceptibility, suggesting that environmental

exposures and epigenetics play major roles. Examples are listed in Fig.

356-1, showing those with HR ≥1.4 and listing them according to their

major known functions. Approximately 50% of known predisposing

genes influence IFN production or function—the most characteristic

increased gene expression pattern of SLE patients. Multiple genes affect

final responses: for example, a gene effect in the promoter for IRF5 that

increases IFN production is associated with SLE in all ancestries, but a

haplotype containing IRF5 and transportin 3 (TNPO3), which probably

further increases IFN responses, is present only in European ancestries.

Some polymorphisms influence clinical manifestations; these are listed

in Fig. 356-1. Some genes relate to end-organ dysfunction rather than

SLE, such as MYH9/APOL1 associating with end-stage renal disease

(ESRD) in all ancestries, whereas APOL1G1/G2 associates with ESRD

(but not SLE) only in African Americans. Such combinations probably

account for lupus nephritis being more common and more severe in

African Americansthan in otherraces. Some gene effects are in promoter

regions (e.g., MYH9/APOL and IL-10), and others are conferred by copy

numbers (e.g., C4A, TLR7). In addition, multiple epigenetic changes

characterize SLE, including hypomethylation of DNA-encoding genes,

promoter regions, and/or transcription factors in CD4+ T cells, B cells,

and monocytes, e.g., genes that control production of type 1 IFNs. In

contrast, some DNA regions in SLE B cells are hypermethylated. There

are also histone modifications in SLE DNA. Some of these changes

are mediated by microRNAs associated with SLE, including some that

control DNA methyltransferases (DNMTs; such as mIR-146a), which

control methylation of DNA in CD4+ T cells and resultant IFN production. Some gene polymorphisms contribute to several autoimmune

diseases, such as STAT4 and CTLA4. Most of these genetic effects

influence immune responses to the external and internal environment;

TABLE 356-1 Autoantibodies in Serum or Plasma in Systemic Lupus Erythematosus (SLE)

ANTIBODY PREVALENCE, % ANTIGEN RECOGNIZED CLINICAL UTILITY

Antinuclear

antibodies

98 Multiple nuclear Best screening test; repeated negative tests by immunofluorescence make SLE

unlikely. Immunofluorescence is best standard test: titers of 1:80 or higher may

separate clinically significant tests from false positives. Has good sensitivity but

poor specificity for SLE.

Anti-dsDNA 70 DNA (double-stranded) High titers are SLE-specific and in some patients correlate with disease activity,

nephritis, vasculitis. Crithidia immunofluorescence is more specific for SLE than

ELISA methods.

Anti-C1q 33 Collagen-like determinants on

complement component C1q

Present in 63% of lupus nephritis, associated with active lupus nephritis especially

when anti-dsDNA is also present. Correlates with activity of nephritis. Not specific

for SLE.

Anti-Sm 25 Protein complexed to 6 species of

nuclear U1 RNA

Specific for SLE; no definite clinical correlations; most patients also have anti-RNP;

more common in blacks and Asians than whites

Anti-RNP 40 Protein complexed to U1 RNA Not specific for SLE; high titers associated with syndromes that have overlap

features of several rheumatic syndromes including SLE; more common in blacks

than whites; correlates with high IFN-induced gene signature

Anti-Ro (SS-A) 30 Protein complexed to hY RNA, primarily

60 kDa and 52 kDa

Not specific for SLE; associated with sicca syndrome, predisposes to subacute

cutaneous lupus and neonatal lupus with congenital heart block.

Anti-La (SS-B) 10 47-kDa protein complexed to hY RNA Usually associated with anti-Ro.

Antihistone 70 Histones associated with DNA (in

nucleosome, chromatin)

More frequent in drug-induced lupus than in SLE.

Antiphospholipid 50 Phospholipids, β2

-glycoprotein 1 (β2

G1)

cofactor, prothrombin

Three tests available—ELISAs for cardiolipin and β2

G1, sensitive prothrombin

time (DRVVT) for lupus anticoagulant; predisposes to clotting, fetal loss,

thrombocytopenia.

Antierythrocyte 60 Erythrocyte membrane Measured as direct Coombs test; a small proportion develops overt hemolysis.

Antiplatelet 30 Surface and altered cytoplasmic

antigens on platelets

Associated with thrombocytopenia, but sensitivity and specificity are not good;

this is not a useful clinical test.

Antineuronal

(includes

antiglutamate

receptor 2)

60 Neuronal and lymphocyte surface

antigens

In some series, a positive test in CSF correlates with active CNS lupus.

Antiribosomal P 20 Protein in ribosomes In some series, a positive test in serum correlates with depression or psychosis

due to CNS lupus.

Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DRVVT, dilute Russell viper venom time; ELISA, enzyme-linked immunosorbent assay.