Autoimmunity and autoimmune diseases mechanisms mangement

1. Autoimmunity and Autoimmune
Diseases
Autoimmune diseases represent a significant health burden for 3% to 9%
of the general population. Consequently, rheumatologists have a great
interest in defining the causes and pathophysiology of autoimmunity and
in applying this information in the clinic. The immune system must
effectively defend against a diverse universe of pathogens while
simultaneously maintaining tolerance to self-antigens.
The term autoimmunity refers to a failure of the body’s immune system
to recognize its own cells and tissues as “self”. Instead, immune
responses are launched against these cells and tissues as if they were
foreign or invading bodies
Autoreactivity is more nuanced, ranging from a low “physiologic” level
of self-reactivity essential for lymphocyte selection and maintenance of
normal immune system homeostasis, to an intermediate level
of autoimmunity that manifests as circulating autoantibodies and tissue
infiltrates that are not associated with clinical consequences, to
pathogenic autoimmunity associated with immune-mediated dysfunction
or injury.
Autoimmune diseases can be classified as systemic or organ-specific
depending on the extent of their clinicopathology. The systemic category
includes systemic lupus erythematosus (SLE), rheumatoid arthritis (RA),
scleroderma, primary Sjögren's syndrome, dermatomyositis, and systemic
vasculitides. In systemic disease, autoimmunity targets ubiquitously
expressed self-antigens, and end-organ injury is typically mediated by
autoantibodies and, less commonly, T cells. In contrast, in organ-specific

2. diseases, the self-antigens are typically cell or tissue specific in location
or accessibility, and end-organ damage can be mediated by antibodies
and/or T cells. Some of the more notable examples in this group, which
span virtually all organ systems, include Hashimoto's thyroiditis, Graves'
disease, multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), anti-
phospholipid syndrome, pemphigus vulgaris, autoimmune hemolytic
anemia, idiopathic thrombocytopenic purpura, and myasthenia gravis.
Central tolerance
During differentiation, T and B cell precursors with self-reactivity are
positively selected in the thymic cortex and bone marrow, respectively,
and those with low avidity for self are exported to the periphery. In
contrast, autoreactive T cells with high avidity for self-antigens expressed
by medullary thymic epithelial cells under the control of AIRE or FEZF2
are deleted or differentiate to Treg cells, while autoreactive B cells are
deleted or receptor-edited. Central tolerance, however, is incomplete, and
some autoreactive T and B cells are exported to the periphery. The
exported cells are normally controlled by peripheral tolerance
mechanisms, including inhibitory molecules, anergy, ignorance and
suppression by Treg cells. However, in genetically-predisposed
individuals, tissue damage, inflammation, and presentation of
sequestered, cryptic, neo self-antigens or microbial mimics might
provoke break of tolerance and autoimmunity.

3. Autoimmune disease susceptibility is multifactorial, involving genetic,
environmental, sex, and other factors, with genetic predisposition usually
playing a central role. The contributions of these factors are typically
heterogeneous, partial, and additive.
Genetic Factors
Three main sets of genes are suspected in many autoimmune diseases.
These genes are related to:
 Immunoglobulins
 T-cell receptors
 The major histocompatibility complexes (MHC).

4. The first two, which are involved in the recognition of antigens, are
inherently variable and susceptible to recombination. These variations
enable the immune system to respond to a very wide variety of invaders,
but may also give rise to lymphocytes capable of self-reactivity.
Certain MHC class II allotypes are strongly correlated with
 HLA DR2 is strongly positively correlated with Systemic Lupus
Erythematosus, narcolepsy and multiple sclerosis, and negatively
correlated with DM Type 1.
 HLA DR3 is correlated strongly with Sjögren's syndrome, myasthenia
gravis, SLE, and DM Type 1.
 HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1
diabetes mellitus, and pemphigus vulgaris. Fewer correlations exist with
MHC class I molecules.
The most notable and consistent is the association between HLA B27 and
ankylosing spondylitis. Correlations may exist between polymorphisms
within class II MHC promoters and autoimmune disease.
Gender bias in autoimmunity
It has long been recognized that most autoimmune diseases exhibit
considerable gender dimorphism with higher incidence in females. Two
major factors are thought to contribute to this dimorphism: gonadal
hormones and direct X chromosome effects. The contribution of sex
hormones has been suggested by the observations that gender bias is
more evident after puberty, and that estrogens enhance while androgens
suppress immune responses and autoimmunity in lupus-predisposed mice.
Female hormones exert broad effects on the expression of multiple
immunologically-relevant genes, including inflammatory cytokines and

5. TLR signaling molecules. Estrogens also interfere with B cell tolerance,
and T cell tolerance may also be affected since AIRE expression in
thymic epithelium was reported to be downregulated by estrogens and
upregulated by androgens. Sex hormones and the microbiota also
influence each other, and gender differences in microbiota composition
may also contribute to gender bias in autoimmunity
Three interconnected mechanisms have been proposed to explain direct X
chromosome contributions to autoimmunity: escape from X-inactivation,
loss of mosaicism, and aneuploidy. X chromosome inactivation is a major
epigenetic event that ensures gene dosage compensation in females
compared to males.
The multiple pathways to autoimmunity
Autoimmunity may result from disturbances in multiple processes acting
singly or in combination. Tissue damage under sterile conditions or due
to infections may lead to availability of nucleic acids and other damage-
or pathogen-associated molecular patterns (DAMPs, PAMPs),
presentation of self-antigens to non-tolerant lymphocytes, and induction
of inflammatory responses. Microbiota dysbiosis may result in
displacement of beneficial commensals, reductions of several anti-
inflammatory factors (short chain fatty acids, SCFA; Aryl hydrocarbon
receptor ligands, AHR-L; polysaccharide A, PSA), expansion of adherent
bacteria (e.g. segmented filamentous bacteria, SFB in mice), damage of
the mucosal/epithelial barrier, and translocation of bacteria and
inflammatory products to mesenteric lymph nodes. These effects lead to
engagement of toll like receptors (TLRs) and other innate sensors,
production of inflammatory cytokines, reduction in Treg cells (TR),
expansion of TH17 and other effector cells, and production of

6. autoantibodies, resulting in organ-specific or systemic autoimmune
diseases.
Nucleic acid sensing as initial trigger of autoimmunity
Nucleic acid sensors are critical innate immune receptors that reside
either in endolysosomes or the cytosol. Upon recognition of specific
ligands, they initiate a signaling cascade resulting in the activation of
several transcription factors that promote cell activation and production
of type I interferons (IFN-I) and inflammatory cytokines.

7. The hidden microbial “self” and autoimmunity
It is postulated that self-nucleic acids in microparticles released from
dying cells or in neutrophil extracellular traps (NETs) gain access to
acidified endolysosomal compartments of pDCs, DCs, and antigen-
specific B cells. TLR engagement and production of inflammatory
cytokines causes upregulation of MHC and costimulatory molecules in
these cells, antigen presentation, and engagement of autoreactive T cells.
Complexes of autoantibodies (IgG, IgE) with nucleic acid-associated
molecules are taken up through the FcR and amplify and sustain the
inflammatory response. In certain instances, microbial nucleic acids alone
or in conjunction with self-nucleic acids released from damaged tissues
may constitute the initial trigger.

8. DIAGNOSIS
Diagnosis of autoimmune disorders largely rests on accurate history and
physical examination of the patient, and high index of suspicion against a
backdrop of certain abnormalities in routine laboratory tests (example,
elevated C-reactive protein). In several systemic disorders, serological
assays which can detect specific autoantibodies can be employed.
Localised disorders are best diagnosed by immunofluorescence of biopsy
specimens. Autoantibodies are used to diagnose many autoimmune
diseases. The levels of autoantibodies are measured to determine the
progress of the disease.

9. TREATMENT
Treatments for autoimmune disease have traditionally been
immunosuppressive, antiinflammatory (steroids), or palliative. Non-
immunological therapies, such as hormone replacement in Hashimoto's
thyroiditis or Type 1 diabetes mellitus treat outcomes of the
autoaggressive response, thus these are palliative treatments. Dietary
manipulation limits the severity of celiac disease. Steroidal or NSAID
treatment limits inflammatory symptoms of many diseases. IVIG is used
for CIDP and GBS. Specific immunomodulatory therapies, such as the
TNFα antagonists (e.g. etanercept), the B cell depleting agent rituximab,
the anti-IL-6 receptor tocilizumab and the costimulation blocker
abatacept have been shown to be useful in treating RA. Some of these
immunotherapies may be associated with increased risk of adverse
effects, such as susceptibility to infection.
Nutrition and Autoimmunity
Vitamin D/Sunlight
Because most human cells and tissues have receptors for vitamin D,
including T and B cells, adequate levels of vitamin D can aid in the
regulation of the immune system.
Omega-3 Fatty Acids
Studies have shown that adequate consumption of omega-3 fatty acids
counteracts the effects of arachidonic acids, which contribute to
symptoms of autoimmune diseases. Human and animal trials suggest that
omega-3 is an effective treatment modality for many cases of Rheumatoid
Arthritis, Inflammatory Bowel Disease, Asthma, and Psoriasis.