Autoimmune connective tissue disease

Autoimmune Disease Causes

The exact causes of autoimmune diseases are complex and often multifactorial, involving genetic predisposition and environmental triggers [1, 2]. Potential mechanisms include [1, 2]:

1. Molecular Mimicry: An infection triggers an immune response against a pathogen (e.g., bacteria, virus). Components (antigenic determinants or epitopes) of this pathogen closely resemble proteins found in normal host tissues. The immune response, initially targeted at the pathogen, cross-reacts with the similar self-tissue, leading to autoimmune attack. Examples include rheumatic fever following streptococcal infection or reactive arthritis after certain infections.
2. Altered Self-Antigens: Tissue damage (necrosis) or modification (e.g., by drugs, toxins, infections) can alter the structure of self-proteins, making them appear foreign to the immune system and triggering an autoimmune response. This may play a role in conditions like autoimmune hepatitis following viral hepatitis.
3. Loss of Immune Privilege/Barrier Breakdown: Some tissues (like the eye, testes, central nervous system, thyroid) are normally separated from the general circulation and immune surveillance by tissue barriers. Damage to these barriers can expose previously "hidden" self-antigens to the immune system, initiating an autoimmune response (e.g., autoimmune thyroiditis). Since these antigens weren't presented during immune system development in the thymus, lymphocytes targeting them may not have been eliminated.
4. Immune Dysregulation: Problems with the mechanisms that normally control immune responses and prevent autoimmunity can lead to disease. This may involve impaired function of regulatory T cells (T-suppressors) or defects in the thymus's ability to eliminate self-reactive lymphocytes. General hyperactivation of the immune system might also contribute.

The specific mechanisms underlying many autoimmune diseases, such as systemic sclerosis or polyarteritis nodosa, are still not fully understood [1]. Many involve delayed-type hypersensitivity reactions mediated by T lymphocytes, while others, particularly those affecting blood cells, are primarily mediated by circulating autoantibodies [1].

Autoantigens can be various molecules, including proteins, DNA (nucleic acids), lipids (phospholipids), sugars, or even other antibodies (e.g., rheumatoid factor attacking IgG) [1]. It's noteworthy that low levels of certain "natural" autoantibodies (often IgM class) exist normally and may play beneficial roles, such as clearing cellular debris or stimulating tissue repair, without causing disease [1].

Autoimmune diseases are broadly categorized as [1]:

1. Organ-Specific: Primarily targeting a single organ (e.g., Hashimoto's thyroiditis, Type 1 Diabetes Mellitus, Addison's disease, pernicious anemia).
2. Systemic (Non-Organ-Specific): Affecting multiple organs and tissues throughout the body (e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, dermatomyositis). Connective tissue is often a primary target in these systemic diseases.

Detecting specific autoantibodies in a patient's serum is a crucial diagnostic tool [1, 2]. While many autoantibodies are not exclusive to one disease, their presence, pattern, and levels (titers) can help confirm a diagnosis, assess disease activity, predict prognosis, guide treatment choices, and monitor therapeutic effectiveness [1, 2].

 

Rheumatic Diseases

Rheumatic diseases encompass a wide range of conditions affecting joints, muscles, bones, and connective tissues [1, 2]. Many systemic autoimmune diseases fall under this category, particularly those known as systemic connective tissue diseases [1]:

• Systemic Lupus Erythematosus (SLE)
• Systemic Sclerosis (Scleroderma)
• Sjögren's Syndrome
• Mixed Connective Tissue Disease (MCTD)
• Polymyositis / Dermatomyositis
• Rheumatoid Arthritis (RA)
• Myasthenia Gravis (primarily neuromuscular, but autoimmune)
• Multiple Sclerosis (MS) (primarily neurological, but autoimmune)
• Antiphospholipid Syndrome (APS)
• Systemic Vasculitides (e.g., Polyarteritis Nodosa - sometimes grouped separately)

 

Rheumatic Disease Laboratory Tests

Laboratory investigations are vital in the diagnosis and management of rheumatic diseases [1, 2]. Key tests include the assessment of:

• Autoantibodies: Specific antibodies targeting self-components (see below).
• Immunoglobulins: Measuring levels of different antibody classes (IgG, IgM, IgA).
• Circulating Immune Complexes (CIC): Complexes formed by antibodies binding to antigens.
• Complement System Components: Proteins involved in the immune response (levels like C3, C4 can be decreased in active SLE).
• Acute Phase Reactants: Markers of inflammation (e.g., C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR)).
• Markers of Endothelial Dysfunction/Injury: Relevant in vasculitis.
• Genetic Markers: Certain genes (e.g., HLA-B27) are associated with increased risk for specific diseases like ankylosing spondylitis.
• Markers of Bone Metabolism: Relevant in assessing bone health affected by disease or treatment.

 

Rheumatoid Factor (RF)

Rheumatoid Factor (RF) refers primarily to autoantibodies (most commonly IgM, but also IgG, IgA, IgE) that target the Fc portion (the "tail" region) of a person's own IgG antibodies [1, 2]. RF is present in approximately 75-80% of patients with Rheumatoid Arthritis (RA) [1, 2]. However, it is not specific to RA and can also be found in other conditions like Sjögren's syndrome, scleroderma, dermatomyositis, certain chronic infections, some cancers (B-cell lymphoproliferative diseases), and even in a percentage of healthy individuals (especially older adults) [1, 2]. In the context of RA, the presence of RF, particularly at high levels, is often associated with more severe disease, including rapidly progressive joint destruction and the development of extra-articular (systemic) manifestations [1, 2].

 

Antibodies to Cyclic Citrullinated Peptide (Anti-CCP)

Antibodies to Cyclic Citrullinated Peptide (Anti-CCP or ACPA) represent a group of autoantibodies directed against proteins containing citrulline, an amino acid modification that occurs during inflammation [1, 2]. Proteins like filaggrin are common targets [2]. Anti-CCP antibodies are highly specific for Rheumatoid Arthritis (present in about 70-80% of RA patients, but much less common in other conditions or healthy individuals) [1, 2]. They are considered more specific for RA than RF [1]. Anti-CCP antibodies often appear very early in the course of RA, sometimes even before symptoms develop, making them valuable for early diagnosis [1, 2]. Furthermore, their presence is associated with a higher likelihood of developing erosive joint disease (more aggressive RA) [1, 2].

 

Antibodies to Modified Citrullinated Vimentin (Anti-MCV)

Antibodies to Modified Citrullinated Vimentin (Anti-MCV) target vimentin, a structural protein found in various cells, including those in the joint lining (synovium) [2]. Vimentin can become citrullinated during inflammation [2]. Anti-MCV antibodies are another marker associated with Rheumatoid Arthritis [2]. They may be present in some RA patients who test negative for RF or anti-CCP, potentially aiding diagnosis in those cases [2]. Some studies suggest anti-MCV may also correlate with disease activity and radiographic progression in RA [2].

 

Circulating Immune Complexes (CIC)

Circulating Immune Complexes (CIC) are formed when antibodies bind to antigens (either self-antigens or foreign antigens like microbes) [1]. Normally, these complexes are efficiently cleared from the circulation by the immune system (reticuloendothelial system) [1]. However, in certain conditions, particularly autoimmune diseases with high levels of autoantibodies or chronic infections, CICs can form excessively or be cleared inefficiently [1]. These complexes can deposit in tissues (like blood vessel walls, kidneys, joints), triggering inflammation and contributing to tissue damage (Type III hypersensitivity reaction) [1]. Elevated levels of CICs can be found in various inflammatory, infectious, and malignant diseases [1]. Measuring CIC levels can be a marker of disease activity in some autoimmune conditions, such as Systemic Lupus Erythematosus (SLE) [1].

 

Frequency of Finding Antibodies (%) in Autoimmune Diseases

Note: Frequencies are approximate and can vary depending on the specific assay and patient population [1, 2]. "-" indicates typically absent or very low frequency.

Disease	Anti-dsDNA	Anti-ssDNA	Anti-Histone	Anti-SS-A (Ro)	Anti-SS-B (La)
Systemic Lupus Erythematosus (SLE)	~60-80+ (highly specific)	Common (~70+)	~50-70	~30-50	~10-15
Drug-induced Lupus	Rare (-)	Common	>95	-	-
Mixed Connective Tissue Disease (MCTD)	Low (~10-30)	Low (~10-30)	-	Occasional	Occasional
Rheumatoid Arthritis (RA)	Rare (-)	Occasional (~30-50 in some reports)	Occasional (~30-50 in some reports)	~10-15 (often with secondary Sjögren's)	Rare (-)
Sjögren's Syndrome	Low (~10-30)	Low (~10-30)	-	~60-70+	~40-50+
Systemic Sclerosis (Scleroderma)	Low (~10-30)	Low (~10-30)	Occasional	~20-30 (esp. limited cutaneous)	Rare (-)
Polymyositis/Dermatomyositis	Low (~10-30)	Low (~10-30)	-	Occasional	Occasional

 

Disease	Anti-Sm	Anti-U1-RNP	Anti-Scl-70 (Topoisomerase I)	Anti-Jo-1 (Histidyl tRNA synthetase)
Systemic Lupus Erythematosus (SLE)	~20-30 (highly specific)	~30-40	Rare (-)	Rare (-)
Drug-induced Lupus	-	-	-	-
Mixed Connective Tissue Disease (MCTD)	Rare (-)	~95-100 (hallmark)	Rare (-)	Rare (-)
Rheumatoid Arthritis (RA)	-	Low (<10)	-	-
Sjögren's Syndrome	-	Low (<10)	-	-
Systemic Sclerosis (Scleroderma)	Rare (-)	Low (~10-15)	~20-40 (specific for diffuse cutaneous SSc)	Rare (-)
Polymyositis/Dermatomyositis	Rare (-)	Occasional	Rare (-)	~20-30 (marker for anti-synthetase syndrome)

 

Differential Diagnosis of Suspected Systemic Autoimmune Disease

 

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References

1. Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell JR. Kelley & Firestein's Textbook of Rheumatology. 10th ed. Elsevier; 2017. Chapters on specific autoimmune diseases and principles of autoimmunity.
2. Fauci AS, Langford CA. Harrison's Principles of Internal Medicine. 20th ed. McGraw Hill; 2018. Section 6: Disorders of the Immune System, Connective Tissue, and Joints.
3. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. 10th ed. Elsevier; 2020. Chapter 6: Diseases of the Immune System.