2.1 Connective Tissue

RA is a chronic systemic inflammatory disease characterized pathologically by symmetrical and persistent polyarticular pain, accompanied by chronic inflammation of the synovial membranes and the formation of vascular pannus [8]. RA leads to cartilage and bone destruction as well as joint inflammation, leading to joint deformities and functional loss. Moreover, systemic inflammation may cause damage to other organs, and have a negative effect on patients’ quality of life [9, 10].

SLE is a heterogeneous systemic autoimmune disease characterized by a wide variety of clinical manifestations, complicating both its assessment and treatment [11]. Patients with SLE produce large amounts of autoantibodies, potentially affecting multiple organs and systems [12]. According to the clinical assessment and diagnostic criteria established by the Systemic Lupus International Collaborating Clinics, the clinical manifestations of SLE can include acute cutaneous lupus, chronic cutaneous lupus, oral or nasal ulcers, nonscarring alopecia, arthritis, serositis, nephritis, hemolytic anemia (HA), and neurological disorders such as seizures [13, 14].

2.2 Exocrine Glands

SS is a chronic disease that primarily affects the exocrine glands, particularly the salivary and lacrimal glands. In addition, the nasal cavity, upper respiratory tract, and female genitalia may be affected. Clinically, the initial symptoms manifest as dryness of the mouth and eyes. Owing to decreased saliva production, patients experience dysphagia, altered taste sensations, oral burning, difficulty speaking continuously, and an urge to wake up at night to drink water. Individuals with SS have an increased incidence of oral infections, gingivitis, and dental caries and often report symptoms such as dryness, itching, pain, and photophobia in the eyes, which are prone to infection. Additionally, parotid gland swelling is common among affected individuals. In addition to affecting the glands, SS affects the skin, joints, lungs, kidneys, muscles, and nerves. This can result in a range of clinical manifestations, including vasculitis, Raynaud's phenomenon, arthritis, arthralgia, interstitial pneumonia, tracheobronchial dryness, interstitial nephritis, lymphoma, myalgia, neuroinflammation, and hemiplegia [15-17].

2.3 Skin

Psoriasis, commonly referred to as psoriasis vulgaris, is a chronic inflammatory skin condition [18]. It is classified into five distinct clinical subtypes: plaque, guttate, inverse, pustular, and erythrodermic. Plaque psoriasis, the most prevalent subtype, is characterized by well-defined, red, itchy plaques on the trunk, limbs, and scalp, with multiple layers of silvery-white scales. Guttate psoriasis presents as small, acute erythematous spots, typically triggered by infections with Group A beta-hemolytic Streptococcus and predominantly affects children and adolescents. Approximately one-third of patients with guttate psoriasis subsequently develop plaque psoriasis [19, 20]. Inverse psoriasis affects intertriginous areas such as the groin, vulva, and axillae, resulting in mildly eroded erythema. Pustular psoriasis is distinguished by the presence of dense, sterile pustules on the skin surface [21, 22]. Erythrodermic psoriasis, the rarest type of psoriasis, often arises from prolonged use glucocorticoids and is associated with severe symptoms, including widespread erythema [23]. Psoriasis is associated with several comorbidities, including psoriatic arthritis, obesity, and metabolic syndrome [24].

SSc is the most fatal rheumatic disease. It is classified into several subtypes, including diffuse scleroderma; limited scleroderma; scleroderma without skin involvement; overlap syndromes (which occur simultaneously with other rheumatologic diseases); and calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias (CREST) syndrome [25, 26]. Early symptoms include skin tightness, itching, Raynaud's phenomenon, arthritis, and muscle pain. Skin lesions progress through three phases: the inflammatory, sclerotic, and atrophic phases. In patients with SSc, the digestive system is the most commonly affected organ system. Patients frequently present with symptoms such as reflux, bloating, constipation, diarrhea, and incontinence. Additionally, pulmonary fibrosis is common in patients with SSc [27]. Other organs, including the heart, kidneys, and thyroid, are also affected in SSc.

Alopecia areata (AA) is a temporary, nonscarring form of hair loss without permanent damage to hair follicles. AA is clinically characterized by round or oval patches of sudden hair loss, typically located on the scalp. This condition occurs when the immune system targets the hair follicles, resulting in inflammation [28].

2.4 Digestive System

Autoimmune liver disease refers to a group of chronic liver conditions caused by disturbances in the body's immune function. This includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and overlap syndromes. Each autoimmune liver disease type presents with distinct clinical manifestations and varying degrees of pathological damage to the liver. AIH is characterized by symptoms such as fatigue, nausea, abdominal pain, and loss of appetite, accompanied by significant jaundice. AIH can progress and may lead to cirrhosis and liver failure [29]. It frequently has an insidious onset, with patients remaining asymptomatic for extended periods. Patients with acute manifestations can develop acute liver failure [29]. PBC is a chronic cholestatic liver disease that presents with nonsuppurative injury to the small bile ducts within the liver and damage to the portal areas. In some cases, patients present with nonspecific symptoms, such as fatigue and itchy skin. PBC can progress to portal hypertension, liver fibrosis, and cirrhosis [30]. PSC causes inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to bile duct strictures and cholestasis. In addition, it is associated with inflammatory bowel disease (IBD). In later stages, patients with PSC present with signs of decompensated cirrhosis, including portal hypertension and liver failure. The risk of PSC recurrence is high, even after liver transplantation. Additionally, patients with PSC have a higher risk of developing cholangiocarcinoma and colorectal cancer [31, 32].

AIG is a chronic inflammatory disease that leads to gastric dysfunction, vitamin B12 and iron malabsorption, and pernicious anemia (which is responsible for the primary symptoms of AIG) [33]. Furthermore, vitamin B12 deficiency affects the gastrointestinal and nervous systems, resulting in symptoms such as diarrhea, glossitis, peripheral neuropathy, weakness, memory loss, and confusion [34]. The lack of gastric acid also contributes to delayed gastric emptying, increasing the risk of gastrointestinal infections [35, 36]. In later stages, AIG is characterized by gastric mucosal atrophy and an elevated risk of gastric neoplasms [37].

IBD is an autoimmune-related idiopathic intestinal inflammatory disorder, clinically characterized by symptoms such as abdominal pain, diarrhea, bloody stools, and weight loss. IBD primarily affects the ileum, rectum, and colon. The main forms are ulcerative colitis and Crohn's disease [38, 39]. Ulcerative colitis involves the rectum, with inflammation limited to the mucosa and submucosa, often accompanied by crypt inflammation and crypt abscesses. In contrast, Crohn's disease can occur in any part of the digestive system; however, it most commonly affects the terminal ileum. It is characterized histologically by thickening of the submucosa, transmural inflammation, fissuring ulcers, and granulomas. Complications of IBD include fibrosis-induced intestinal strictures and obstruction as well as an increased risk of colorectal cancer [40-42]. Furthermore, patients with IBD experience various extraintestinal manifestations including ocular conditions such as uveitis and scleritis; skin and mucosal lesions such as erythema nodosum and pyoderma gangrenosum; arthritis; low bone mass and osteoporosis; liver and pancreaticobiliary disorders such as PSC, nonalcoholic fatty liver disease, and acute pancreatitis; and portal vein thrombosis [43, 44].

2.5 Endocrine System

T1D, characterized by the destruction of pancreatic β-cells and insufficient insulin production, primarily affects children and adolescents [45, 46]. Delayed treatment or inadequate disease management may hinder children's development. Patients have high blood glucose levels, and symptoms such as polyuria, polydipsia, polyphagia, and weight loss [47]. Acute T1D complications include diabetic ketoacidosis, hypoglycemia, and infections. Additionally, the improper use of insulin injections may lead to chronic complications such as joint disorders, cataracts, and osteoporosis. Chronic complications such as macrovascular and microvascular diseases, as well as neuropathy, are significant contributors to diabetes-related disability and mortality [48].

Autoimmune thyroid disease (AITD) refers to a group of disorders in which the immune system attacks thyroid antigens, leading to lymphocytic infiltration of the thyroid tissue. The most common forms of AITD are Graves’ disease (GD) and HT [49]. GD, also known as toxic diffuse goiter, is characterized by hyperthyroidism caused by abnormal antibodies that activate thyroid-stimulating hormone receptors, resulting in thyroid hyperplasia. However, a small percentage of patients with GD present with thyroid dysfunction [50]. Symptoms associated with GD include hyperthyroidism, mucinous edema of the skin, reproductive system abnormalities, and Graves’ orbitopathy [51]. The latter is an important extrathyroidal manifestation of GD, in which patients experience prominent exophthalmos, photophobia, pain, and conjunctival or corneal lesions [52]. In contrast, in HT, the immune system attacks thyroid follicular cells, leading to hypothyroidism. Clinically, HT presents as an enlarged, firm, and grayish thyroid gland that compresses the neck, resulting in difficulties with speech, breathing, and swallowing. Additional symptoms include constipation; pseudo-obstruction; intestinal obstruction; dry, yellowed, and thickened skin; muscle pain and spasms; and anemia [53].

2.6 Hematologic System

AIHA is a type of HA caused by immune system dysfunction, in which antibodies and/or complement against self-red blood cells are produced and bind to red blood cell membrane antigens, accelerating the destruction of red blood cells. It is mostly chronic extravascular hemolysis, with a slow onset and more common in adult women. It is characterized by anemia, jaundice, and splenomegaly. One-third of the patients have anemia and jaundice, more than half have mild to moderate splenomegaly, and one-third have hepatomegaly [54].

2.7 Neuromuscular System

MS is an autoimmune disease primarily characterized by inflammatory demyelinating lesions in the white matter of the central nervous system [55]. Patients with MS develop demyelinating plaques within the periventricular white matter, optic nerves, spinal cord, brainstem, and cerebellum [56]. Clinically, MS presents as muscle weakness, optic neuritis, nystagmus, sensory disturbances, and bladder dysfunction [57, 58]. Based on disease progression, the National Multiple Sclerosis Society (USA) classifies MS into four types: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive-relapsing (PR) [59]. The RR type is characterized by relapses in the early stages, followed by periods of remission. Over time, many patients with long-standing RR transition to the SP type, in which the condition worsens without remission. The PP type manifests in middle to late adulthood, leading to a gradual decline in function. The PR type is relatively rare and is similar to PP but with acute relapses.

MG is an autoimmune disease characterized by dysfunction in transmission at the neuromuscular junction. This occurs when antibodies bind to acetylcholine receptors or other functionally related molecules on the postsynaptic membrane, disrupting normal signal transmission and leading to partial or generalized skeletal muscle weakness and easy fatigue [60]. The primary muscles that are weakened in MG include the extraocular, bulbar, limb, and axial muscles. Approximately 60% of affected individuals initially present with symptoms such as ptosis or diplopia, which may progress to ocular MG over time [61]. In addition, patients with MG experience swallowing and chewing difficulties, limb weakness, and respiratory distress [62]. In the early stages of MG, the majority of patients have thymic hyperplasia, which can progress to thymic atrophy or thymoma. Therefore, thymectomy is commonly performed to alleviate symptoms in patients with MG [63]. Furthermore, approximately 15% of patients with MG develop comorbidities such as thyroiditis and SLE [64].

2.8 Urinary System

Glomerulonephritis is a heterogeneous group of diseases characterized by clinical features such as hematuria, proteinuria, hypertension, edema, oliguria, and varying degrees of renal dysfunction [65]. Pathologically, it is marked by inflammation of the glomeruli and hypercellularity, which can lead to secondary kidney damage [65]. Based on different pathogenic mechanisms, glomerulonephritis is broadly classified into several categories: immune complex-mediated glomerulonephritis, antineutrophil cytoplasmic antibody-associated glomerulonephritis, antiglomerular basement membrane glomerulonephritis, C3 glomerulopathy, and monoclonal immunoglobulin-related glomerulonephritis [66-68]. With the exception of monoclonal immunoglobulin-related glomerulonephritis, all glomerulonephritis subtypes are associated with varying degrees of autoimmune dysregulation. Glomerulonephritis can also be classified based on the clinical type [69]. Clinically, the most common form of glomerulonephritis is acute glomerulonephritis, caused by streptococcal infection, with the incidence being highest in children living in regions and countries with poor sanitary conditions [70]. Glomerulonephritis-related complications include severe congestion, heart failure, hypertensive encephalopathy, and acute renal failure.

3.1 Basic Composition and Functions of the Immune System

The immune system is a sophisticated and dynamic network of cells, tissues, and molecules that collectively safeguard the body against infection, eliminate abnormal cells, and maintain internal stability [73]. Composed of innate and adaptive immune components, it operates through specialized cell development, activation, and function. The innate immune system provides rapid, nonspecific defense mechanisms, whereas the adaptive immune system offers precise, long-lasting immunity through antigen-specific responses [74]. Together, these systems perform three critical functions: immune defense, which protects against external pathogens; immune surveillance, which identifies and eliminates abnormal cells such as tumors; and immune homeostasis, which ensures the balance and stability of the internal environment. This intricate interplay of components and functions highlights the essential role of the immune system in maintaining health and preventing disease.

3.1.1 Basic Composition of the Immune System

The immune system is composed of immune organs, immune cells, and immune molecules, which work together to maintain immune homeostasis and defend the body against pathogens (Figure 2).

3.1.1.1 Immune Organs

Immune organs are sites in which immune cells are generated, develop, mature, and function. They are divided into central and peripheral immune organs [75].

Central immune organs include the bone marrow and thymus. The bone marrow is the site in which hematopoietic stem cells differentiate into various blood cells and immune cells, and B lymphocytes mature. The thymus is the central site for the differentiation, development, and maturation of T lymphocytes. Lymphoid stem cells migrate to the thymus, undergo a complex selection process, and differentiate into immunocompetent T lymphocytes.

Peripheral immune organs primarily include lymph nodes, the spleen, and mucosa-associated lymphoid tissue (MALT). Lymph nodes filter lymph and remove pathogens, serving as important sites for housing lymphocytes and immune responses. The spleen filters blood, clears aged red blood cells and pathogens, and activates immune cells to initiate immune responses. MALT, distributed in mucosal areas such as the respiratory and digestive tracts, forms the first line of defense against pathogen invasion.

3.1.1.2 Immune Cells

Immune cells carry out the work of the immune system and can be divided into innate and adaptive immune cells. Innate immune cells include phagocytes (such as neutrophils and macrophages), natural killer (NK) cells, and dendritic cells (DCs). Phagocytes eliminate pathogens through phagocytosis, whereas DCs are antigen-presenting cells that activate naïve T lymphocytes and initiate adaptive immune responses. NK cells directly kill virus-infected cells and tumor cells, playing a crucial role in immune surveillance [76]. Adaptive immune cells consist mainly of T and B lymphocytes. T lymphocytes can be further divided into helper T cells, cytotoxic T cells (CTL), and Tregs, which are responsible for immune regulation, target-cell killing, and maintaining immune homeostasis, respectively. B lymphocytes differentiate into plasma cells on antigen stimulation, producing antibodies that mediate humoral immunity [77].

3.1.1.3 Immune Molecules

Immune molecules are essential components of the immune system, assisting immune cells in carrying out immune responses. They include antibodies, the complement system, and cytokines.

Antibodies, produced by B lymphocytes, are Y-shaped proteins critical to adaptive immunity. Their variable regions enable precise antigen recognition, neutralizing pathogens through toxin blockade and inhibiting viral entry. Simultaneously, the constant (Fc) region mediates effector functions: opsonizing pathogens for phagocyte clearance, activating the complement cascade, and forming immune complexes for neutrophil recruitment. This dual targeting (antigen binding and immune activation) ensures coordinated pathogen elimination [78].

The complement system, activated through three distinct pathways (classic via antigen–antibody complexes, alternative via spontaneous hydrolysis, and lectin via pathogen carbohydrate recognition), executes a multifaceted immune defense. In addition to directly lysing pathogens through membrane attack-complex formation, it enhances phagocytosis by opsonizing microbes with C3b fragments and amplifies inflammatory responses via anaphylatoxins (C3a, C5a) that recruit leukocytes. Additionally, complement coordinates with adaptive immunity by solubilizing immune complexes and priming B-cell responses, while regulatory proteins prevent host tissue damage through controlled activation cascades [79].

Cytokines such as interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), and chemokines, act as molecular messengers orchestrating immune dynamics. Secreted by immune cells (e.g., T cells, macrophages) and stromal cells, they regulate immune cell activation, proliferation, and differentiation via autocrine, paracrine, or endocrine signaling. For example, IFNs prime antiviral defenses by inducing antiviral protein synthesis, whereas TNF-α drives inflammation and leukocyte recruitment. Additionally, cytokines coordinate innate and adaptive immunity by modulating antigen presentation (IL-12) and antibody class-switching (IL-4 and IL-6). Their pleiotropic effects, mediated through janus kinase (JAK)–signal transducer and activator of transcription (STAT) or nuclear factor kappa-B (NF-κB) pathways, balance proinflammatory and anti-inflammatory responses, ensuring targeted pathogen clearance while preventing immunopathology [80].

3.2 Immune Tolerance

The immune system is dedicated to detecting and eliminating foreign antigens while coordinating both proinflammatory and anti-inflammatory responses. This dynamic equilibrium is known as immune homeostasis, a state essential for maintaining overall health [89]. The disruption of immune homeostasis can lead to infections and tumor development due to impaired immune responses (immunodeficiency), whereas excessive immune responses may result in autoimmune disorders. Despite the presence of self-reactive T and B cells in healthy individuals, lymphocytes coordinate with other immune cells through a tightly regulated network to suppress autoimmunity and maintain tissue integrity. The balance of the immune system is maintained through central and peripheral tolerance mechanisms targeting T and B cells. Central tolerance eliminates potentially autoreactive T cells through negative selection in primary lymphoid organs, the bone marrow, and thymus [90]. Despite the stringency of central tolerance, significant numbers of autoreactive lymphocytes persist in the circulation of healthy individuals and retain the capacity to trigger autoimmunity [91]. Unwanted peripheral immune responses are suppressed through Treg-mediated deletion and induction of anergy, mechanisms that constitute peripheral tolerance [92]. The mechanisms underlying immune tolerance encompass clonal deletion, anergy, immune regulation, and ignoring them. Therefore, the integrated mechanisms of central and peripheral tolerance establish and sustain immune homeostasis.

3.2.1 Central Tolerance

3.2.1.1 T-Cell Tolerance

Central tolerance of T cells occurs in the thymus, effectively preventing the escape of self-reactive cells to the periphery and reducing the tendency toward autoimmunity. Bone marrow-derived progenitors migrate to the thymus, where T-cell antigen receptor (TCR) gene rearrangement at the CD4 and CD8 double-negative stage generates either αβ or γδ progenitors with a diverse TCR repertoire capable of recognizing various antigens. Some αβ progenitors develop into CD4 and CD8 double-positive (DP) thymocytes while acquiring functional TCR expression. DP thymocytes that exhibit high affinity for peptide–MHC complexes on thymic cortical epithelial cells (cTECs) receive survival signals and differentiate into either CD4+ or CD8+ single-positive T cells during positive selection (Figure 3). Those that fail to interact with peptide–MHC complexes undergo apoptosis [93]. This process endows CD4+ or CD8+ T cells with MHC class I/II restriction specificity.

Following positive selection, T cells undergo further screening in the thymic medulla based on the affinity of their TCRs for self-peptide–MHC complexes [94]. This process, termed negative selection, is mediated by thymic antigen-presenting cells (APCs), including specialized medullary thymic epithelial cells (mTECs), DCs, and B cells (Figure 3).

T cells exhibiting high-affinity binding to self-peptide–MHC complexes undergo developmental arrest and clonal deletion, a process critical for eliminating autoreactive precursors [95]. Thymocytes engaging self-peptide–MHC complexes with intermediate affinity differentiate into Tregs, which suppress effector T-cell (Teff) activation [96]. whereas low-affinity interactions permit positive selection of conventional T cells, which subsequently egress from the thymus into peripheral circulation. Since central tolerance is established exclusively within the thymus, robust negative selection necessitates broad self-peptide presentation by thymic APCs [97]. mTECs express the autoimmune regulator (Aire) transcription factor, which plays a crucial role in central tolerance by regulating the expression of tissue-specific antigens [98].

3.2.1.2 B-Cell Tolerance

In the bone marrow, progenitor cells committed to the B-cell lineage undergo V(D)J recombination of immunoglobulin germline genes, a process that generates diverse B-cell antigen receptors (BCRs) essential for adaptive immunity [99]. Despite this diversity serving as the foundation for immune recognition, a substantial proportion (55–75%) of immature B cells exhibit self-reactivity during development [100]. To establish central tolerance, immature B cells undergo stringent selection through three interconnected mechanisms: clonal deletion, anergy, and receptor editing.

Immature B cells expressing autoreactive BCRs that engage high-affinity self-antigens undergo developmental arrest and clonal deletion via apoptosis [101]. In contrast, low-affinity BCR-self-antigen interactions fail to reach the activation threshold required for positive selection, inducing anergy instead [102]. Secondary immunoglobulin gene rearrangement, another tolerance mechanism, modifies autoreactive BCRs to generate variants with reduced self-antigen affinity [103]. The remaining immature B cells, which do not engage self-antigens at levels sufficient to trigger central tolerance, are permitted to mature and migrate to peripheral tissues such as the spleen and lymph nodes. In the periphery, these cells rapidly undergo additional tolerance checks to prevent tissue damage [104].

Although central tolerance mechanisms effectively eliminate the majority of self-reactive T and B cells during thymic and bone marrow development, a subset of autoreactive clones specific for developmentally restricted antigens or inducible antigens escapes central tolerance checks [105]. This residual autoreactivity necessitates a second layer of control: peripheral tolerance, which actively suppresses the activation and effector functions of circulating self-reactive lymphocytes.

3.3 Triggers of Autoimmune Responses

Autoimmune diseases arise owing to a combination of genetic susceptibility, environmental exposures, and breakdowns in immune tolerance.

Genetic predisposition serves as a foundational risk: Polymorphisms in human leukocyte antigen (HLA)/MHC genes (such as HLA-DR4 in RA) alter self-antigen presentation, increasing the likelihood of autoreactive T-cell activation [140, 141]. Non-HLA genes, such as PTPN22 (affecting lymphocyte signaling) and STAT4 (which modulates IFN responses), further disrupt immune checkpoint regulation [142, 143]. These genetic variants collectively lower the threshold for immune dysregulation but rarely trigger autoimmunity on their own.

Environmental cofactors, including pathogens such as Epstein–Barr virus (EBV) and Streptococcus pyogenes, promote autoimmunity by molecular mimicry (e.g., EBV nuclear antigen-1 cross-reacts with lupus-associated autoantigens) or bystander activation during tissue damage [144, 145]. Smoking is also a risk factor for autoimmune disease [146, 147]. Chemical triggers, including silica dust, mercury, and drugs such as procainamide, induce oxidative stress, modify self-proteins into neoantigens, or dysregulate epigenetic controls on genes responsible for the immune response [148, 149]. Ultraviolet radiation, hormonal fluctuations (e.g., estrogen-driven lupus flares), and chronic stress exacerbate these effects by causing cytokine imbalances (e.g., elevating IL-6 and TNF-α) and impairing Treg suppressive capacity [150-152].

The interplay of genetic and environmental factors disrupts immune homeostasis. Tregs, essential for restraining autoreactive lymphocytes, become numerically or functionally deficient, whereas DCs and B cells transition toward proinflammatory states. This shift creates a permissive microenvironment in which self-tolerance erodes, setting the stage for persistent autoreactivity [153]. These systemic imbalances mark the transition from preclinical susceptibility to active autoimmunity, priming the immune system for the uncontrolled inflammation and tissue targeting detailed in the disease progression pathways.

3.4 Pathogenic Progression in Autoimmunity

The progression of autoimmune diseases involves a cascade of pathogenic events that extend beyond the initial breakdown of immune tolerance. Although genetic susceptibility and environmental factors prime the immune system for autoreactivity, the ultimate clinical manifestations arise from three interrelated processes: (1) the production of pathogenic autoantibodies, (2) dysregulated cytokine networks, and (3) irreversible tissue injury. These effector phases often coexist and amplify each other, creating self-perpetuating cycles of inflammation and damage that characterize chronic autoimmunity (Figure 4). The specific pathological outcomes in a given disease context depend on which molecular and cellular pathways dominate, leading to diverse clinical presentations despite shared underlying pathogenic mechanisms.

4.1 Clinical History and Physical Examination

A thorough medical history and physical examination are fundamental in the diagnostic workup of autoimmune diseases. Patients often present with nonspecific symptoms such as fatigue, low-grade fever, and weight loss, but certain disorders exhibit characteristic clinical features as detailed in the previous section. For example, SLE may manifest with malar rash, photosensitivity, arthritis, and renal involvement [11], whereas RA typically presents with symmetric small-joint swelling and morning stiffness [8]. Neurological symptoms, such as vision loss or motor weakness, may suggest demyelinating lesions due to MS [57]. Additionally, family history, history of prior infections, and medication use (e.g., drug-induced lupus from antiarrhythmic drugs) should be carefully assessed to aid the differential diagnosis.

4.2 Laboratory Investigations

Laboratory testing, including testing levels of nonspecific inflammatory markers and disease-specific autoantibodies, plays a key role in the diagnosis of autoimmune diseases.

4.3 Imaging Techniques

In autoimmune diseases, imaging is indispensable for assessing organ damage, disease extent, and treatment response. Imaging modalities range from conventional radiography to advanced functional imaging, each offering unique insights into pathophysiology and guiding precision medicine. Below, we highlight key applications across representative autoimmune disorders.

4.4 Histopathological Evaluation

Tissue biopsy remains the gold standard for diagnosing many autoimmune conditions. In SLE, skin biopsy may show immunoglobulin deposition at the dermoepidermal junction (lupus band test), whereas in AIH, liver biopsy typically reveals interface hepatitis and plasma cell infiltration. Colon biopsy distinguishes Crohn's disease (noncaseating granulomas) from ulcerative colitis (continuous mucosal inflammation). Renal biopsy is indispensable for classifying lupus nephritis and guiding treatment.

Most autoimmune diseases are diagnosed using internationally accepted criteria, such as the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification for SLE, and the 2010 ACR/EULAR criteria for RA. These frameworks combine clinical, serological, and imaging findings to enhance diagnostic accuracy. However, some conditions (e.g., undifferentiated connective tissue disease) may not fulfill the criteria, necessitating longitudinal follow-up to make the diagnosis. Furthermore, diagnostic challenges persist, including false-positive/false-negative antibody results and the absence of specific biomarkers for certain diseases (e.g., seronegative spondyloarthropathies). Emerging technologies such as multiomics (proteomics, metabolomics) and artificial intelligence hold promise for refining diagnostic precision.

5.1 Broad-Spectrum Anti-Inflammatory Drugs (Unselective Targeting)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the initial treatment of autoimmune diseases because of their rapid anti-inflammatory and analgesic effects. They function by inhibiting cyclooxygenase (COX), which has two isoforms: COX-1 and COX-2 [187, 188]. COX-1 is constitutively expressed in most tissues and is responsible for producing prostaglandins that maintain normal physiological functions, such as protecting the gastrointestinal mucosa and regulating renal blood flow [189]. In contrast, COX-2 is inducible and primarily involved in prostaglandin synthesis during inflammation [190]. However, NSAIDs only alleviate symptoms and do not address the underlying cause of the disease or control its activity and progression. Their nonspecific inhibition of the COX pathway affects prostaglandin production throughout the body and lacks cellular or molecular specificity. Traditional NSAIDs, such as ibuprofen and naproxen, inhibit both COX-1 and COX-2, effectively reducing inflammation but increasing the risk of gastrointestinal and renal adverse reactions [191]. In comparison, selective COX-2 inhibitors such as celecoxib have less gastrointestinal toxicity. For example, in a randomized, controlled comparative study, the incidence of ulcers was 2.6% among patients taking celecoxib [192]. Celecoxib is widely used for treating RA and ankylosing spondylitis (AS), effectively relieving pain and improving patients' quality of life. However, the elevated risk of cardiovascular disease, and the withdrawal of rofecoxib owing to the increased risk of thrombotic events, suggests that COX-2 inhibitors should be used with caution [193].

Glucocorticoids are essential for treating severe autoimmune disease and refractory cases, offering broad anti-inflammatory and immune-regulatory effects. They control acute lesions by reducing key proinflammatory cytokines such as IL-1 and IL-6, inhibiting IL-2 production and proliferation of T cells, inhibiting neutrophil and monocyte chemotaxis, and lessening lysosomal enzyme release [194-196]. Extensive studies have confirmed their effectiveness for relieving symptoms, enhancing physical function, and improving quality of life [197]. However, glucocorticoids have serious adverse effects, including post-withdrawal relapses, inability to prevent bone destruction, and increased risk of infection, cardiovascular and cerebrovascular disease, and osteoporosis [198]. Currently, glucocorticoids remain fundamental for inducing remission in RA and SLE [199, 200]. In chronic management, glucocorticoids are often combined with disease-modifying antirheumatic drugs (DMARDs) to rapidly control disease activity while waiting for the DMARDs to take effect [201].

First-line synthetic DMARDs include methotrexate (MTX), which is used for treating RA, leflunomide (LEF), and azathioprine [202]. Cyclophosphamide and mycophenolate mofetil are reserved for treating severe autoimmune diseases (such as lupus nephritis) [203]. The chemical structure and pharmacological mechanism of action of traditional DMARDs differ. MTX inhibits dihydrofolate reductase and reduces tetrahydrofolate formation, blocking DNA synthesis, and can delay joint damage and enable repair of bone damage, so it is suitable for use in treating active RA [204]. LEF mainly inhibits dihydroorotate dehydrogenase activity and affects lymphocyte pyrimidine synthesis, which can improve symptoms in patients with RA [205]. However, both MTX and LEF have slow onset of action, leading to gradual reduction in the symptoms and signs after several weeks or months, and thus require long-term continuous administration.

Natural product-derived drugs can have both broad-spectrum anti-inflammatory properties and certain molecular-targeted effects. Tripterygium wilfordii, a traditional Chinese medicinal herb, contains active compounds such as celastrol, which exhibit potent anti-inflammatory effects [206]. Celastrol inhibits the NLRP3 inflammasome, a key component in triggering the inflammatory response [207]. Preclinical studies have demonstrated that Tripterygium wilfordii can significantly reduce synovitis in RA models, highlighting the value of traditional medicine in treating inflammation [208]. Cp-25, a novel derivative of paeoniflorin, is under investigation as an immunomodulator. It has been found to regulate the B-cell-activating factor (BAFF)-TNF-α pathway and to target TNF receptor-associated factor 2 (TRAF2) and p52 in the NF-κB signaling axis without causing B-cell exhaustion. This selective effect preserves normal B-cell function while inhibiting the pathological immune response [209].

5.2 Molecular-Targeted Therapy

The rise of molecular-targeted therapy has transformed the treatment of autoimmune disease treatment from broad-spectrum inhibition to precise intervention. This kind of therapy can effectively control inflammation and significantly reduce systemic toxicity by specifically targeting key molecules in pathogenic signaling pathways, providing patients with better treatment options.

The emergence of targeted small-molecule inhibitors has changed the therapeutic landscape of autoimmune diseases and provided a new mechanism of action for oral treatment. JAK–STAT inhibitors are a major advance in this category. The JAK–STAT pathway is essential for the signaling of many cytokines and growth factors involved in immune regulation. Tofacitinib, a selective inhibitor of JAK1 and JAK3, is effective in RA treatment [210]. In the RA beam trial, baricitinib, which inhibits JAK1 and JAK2, showed an advantage over adalimumab in patients with MTX-resistant RA [184]. Phosphodiesterase 4 (PDE4) inhibitors such as apremilast provide another targeting method by increasing intracellular cyclic adenosine monophosphate (cAMP) levels, thereby regulating the IL-23/th17 axis [211]. This mechanism is particularly relevant in psoriasis and psoriatic arthritis, in which Th17-mediated inflammation plays a central role. Clinical trials showed that 33% of patients with psoriasis improved the psoriasis area and severity index (PASI75) by 75% after 16 weeks of apremilast treatment [212].

By targeting key molecules with high affinity, mAbs show unique value in treating severe or refractory autoimmune disease. They can accurately recognize and bind specific cytokines, receptors, or cell surface molecules, thus achieving precise regulation of the immune response process. TNF-α antagonists represented by adalimumab, infliximab, and golimumab effectively inhibit proinflammatory signaling by blocking the interaction between TNF-α and its receptors, significantly reducing joint destruction and skin inflammation in diseases such as RA, psoriatic arthritis, and IBD [186, 213]. Rituximab decreases B-cell-mediated autoimmune responses by targeting CD20 molecules on B cells and is used in the treatment of RA and SLE [185]. Belimumab targets BAFF to reduce cell-mediated autoimmune responses [214]. Inebilizumab rapidly depletes CD19+ B cells by binding to CD19 antigen, thereby inhibiting the inflammatory response [215]. Secukinumab is suitable for the treatment of psoriasis and psoriatic arthritis in adults who have had an inadequate response to conventional synthetic DMARDs, and for treating axial spondyloarthritis, including AS and nonradiographic axial spondyloarthritis by targeting IL17A [216]. Bimekizumab is the first dual targeting IL-17A/F antibody, and the 16-week American College of Rheumatology 50% improvement rate (ACR50) in TNF-α inhibitor-refractory psoriatic arthritis was 46% in one study [217]. Tocilizumab and Sarilumab, which target IL-6 receptors, are approved for treating moderate to severe RA [218]. Ulinumab is a fully human mAb against IL-12 and IL-23 receptors, which can block intracellular signal transduction and avoid inflammatory events and T-cell activation [219]. Guselkumab (Tremfya), a mAb targeting IL-23, is a fully human dual-effect mAb. It can block IL-23 activity and bind to the CD64 receptor on IL-23-producing cells. It has been approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis [220]. Mirikizumab (Omvoh), a humanized IgG4 anti-IL-23p19 mAb, inhibits the IL-23 pathway by targeting the p19 subunit of IL-23 and is used to treat ulcerative colitis [221]. The IL-1β neutralizing antibody, kanamab, is used for the treatment of autoinflammatory diseases such as systemic juvenile idiopathic arthritis [222]. These mAbs, through precise targeting, enhance therapeutic effects and reduce adverse reactions, offering better options for patients with autoimmune disease.

Recombinant proteins can achieve multitarget immune regulation by modulating the biological activity of endogenous proteins through molecular simulation or functional regulation. Among them, Fc fusion protein-engineering-technology significantly prolongs serum half-life and enhances therapeutic effectiveness through IgG constant region fusion [223]. The currently established recombinant protein therapies include: (1) the IL-1 receptor antagonist, anakinra, which competitively inhibits the binding of IL-1α/β to type I receptors and exerts anti-inflammatory effects in RA and cold pyridine-related periodic syndrome [224]; (2) the TNF-α inhibitor, etanercept, which neutralizes the proinflammatory factor TNF-α in the form of soluble receptors and is widely used in the treatment of autoimmune diseases [225]; (3) the CTLA-4–Fc fusion protein, abatacept, whose extracellular domain can block the CD28–CD80/86 costimulatory pathway, thereby inhibiting T-cell activation [226]; (4) the dual inhibitor of the B lymphocyte stimulator (BLyS)-A PRoliferation-Inducing Ligand (APRIL), atacicept, which regulates B-cell differentiation and autoantibody production by targeting key B-cell activation factors BLyS and APRIL, and has unique value in the treatment of SLE and immunoglobulin A nephropathy [227, 228]. Research on the molecular mechanisms of these treatment strategies has confirmed that recombinant proteins can provide highly targeted biological treatment options for autoimmune diseases by precisely intervening in the activation pathways and cytokine networks of immune cells, including T cells, B cells, and APCs.

5.3 Cell-Targeted Therapy

Cell-targeted therapy is an emerging field in the treatment of autoimmune diseases, which achieves precise regulation of immune responses by specifically targeting subpopulations of immune cells.

Hematopoietic stem cell transplantation (HSCT) is an advanced method to treat autoimmune diseases by clearing abnormal immune cells and rebuilding the normal immune system. HSCT usually includes three steps: immune elimination, hematopoiesis, and immune reconstitution [229]. Before transplantation, patients received high-dose chemotherapy or radiotherapy to clear abnormal immune cells, followed by infusion of autologous or allogeneic hematopoietic stem cells, which engraft in the bone marrow and differentiate into new blood cells, including immune cells, thereby rebuilding the immune system. Initial lymphocyte depletion can reduce the immune memory pool, including autoreactive clones, followed by profound immune renewal through hematopoiesis and regeneration of the immune system [230]. This approach offers the possibility of long-term remission of autoimmune diseases. The stem cell source of HSCT can be patients themselves (autologous transplantation) or a matched donor (allogeneic transplantation) [231]. Autologous transplantation avoids graft-versus-host disease (GVHD) but may lead to recurrence due to stem cell defects. For example, in SSc, autologous HSCT can significantly improve skin score and lung function, but some patients still experience fluctuations in their autoantibody spectrum, indicating incomplete establishment of immune tolerance [232, 233]. In MS, autologous HSCT can lead to long-term remission and is more effective than drugs such as fingolimod and ocrelizumab, especially in patients with high disease activity [234, 235]. Allogeneic transplantation requires long-term immune suppression and carries a high risk of GVHD. New preconditioning regimens such as antibody–drug conjugates can reduce myelotoxicity, promote donor stem cell implantation, and provide a safer option for treating malignant diseases such as acute leukemia [236]. In addition, HLA-DQ heterodimers may affect the immune response after transplantation and need to be included in the evaluation of typing [237].

Chimeric antigen receptor (CAR) T-cell therapy is a clinically validated method of cellular immunotherapy. Through genetic engineering, patients' cells are transformed to express specific CAR molecules, which can target pathogenic cells that clear specific antigens. In recent years, this technology has been extended to the field of autoimmune diseases, especially autologous CAR-T cell therapy targeting CD19 antigen [214]. For example, in a clinical trial of pediatric SLE, 20 patients treated with CD19–CAR-T achieved clinical improvement, and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 15 patients fell below 4 within 3 months [238]. Deep depletion of B cells, including elimination of self-reactive B-cell clones, is considered a prerequisite for successful CAR-T cell therapy targeting CD19 or B-cell-maturation antigen (BCMA) [238]. Therefore, only diseases driven by B cells, such as SLE, idiopathic inflammatory myopathies, and SSc respond to CAR-T cell therapy [239, 240], and CAR-T cell therapy targeting B cells has little effect on chronic inflammatory diseases lacking pathogenic B cells, such as psoriasis, IBD, and spinal arthritis [241]. In addition, researchers have developed chimeric autoantibody receptor T cells (CAAR-T) technology to precisely target pathogenic B-cell subsets and reduce their impact on normal B cells. Preclinical studies have shown that CAAR-T can significantly reduce the levels of autoantibodies in patients with SLE and also reduce the risk of infection caused by B-cell depletion [242, 243]. In addition, BCMA-CD19 bispecific CAR-T cell therapy showed significant therapeutic effects in patients with SLE/LN. All patients who received sufficient initial dose therapy achieved asymptomatic and drug-free remission at 46 months of follow-up [244]. These advances indicate that CAR-T therapy has broad application prospects in the treatment of autoimmune diseases. Future research will further optimize the design of CAR-T cells and improve their therapeutic effectiveness and safety.

Tregs play a key role in maintaining immune tolerance and preventing autoimmune responses. Tregs mainly inhibit the activation and proliferation of Teffs by secreting inhibitory cytokines such as IL-10 and TGF-β, as well as through direct cell-cell contact [245, 246]. In recent years, immunotherapy targeting Tregs has shown great potential in the treatment of autoimmune diseases [247], and adoptive-transfer Treg therapy has shown good therapeutic effects for treating various autoimmune diseases. For example, in a clinical study of T1D, adoptive-transfer of Tregs significantly prolonged the survival time of pancreatic β-cells [248, 249]. In addition, in animal models of diseases such as SLE and Crohn's disease, adoptive-transfer of Treg therapy has been shown to reduce disease manifestations and inflammatory responses [250, 251]. These studies have shown that engineering Treg cells can enhance their function and specificity, thereby improving the accuracy and effectiveness of treatment. Currently, researchers are developing antigen-specific Treg therapies. This method aims to expand or genetically engineer Tregs in vitro so that they can specifically recognize and respond to self-antigens, thereby more effectively inhibiting autoimmune responses in vivo [252].

In recent years, an increasing number of studies have revealed that gut microbiota affects immune homeostasis by regulating the differentiation of T and B cells. For example, the amplification of specific gut microbiota in patients with SLE is directly related to the production of autoantibodies, such as anti-dsDNA antibodies [253-255]. In experimental autoimmune encephalomyelitis (EAE), overactivation of dopamine D2 receptors in intestinal epithelial cells leads to dysbiosis of the microbiota, which exacerbates central nervous system inflammation through activation of microglia [256, 257]. Short chain fatty acids, such as butyric acid, regulate Treg differentiation and alleviate inflammatory responses in EAE and RA by inhibiting histone deacetylase activity [258, 259]. Probiotics such as oligofructose can selectively promote the proliferation of anti-inflammatory bacteria and restore Th17/Treg balance [260, 261]. Clinical studies have shown that fecal microbiota transplantation has a regulatory effect on Th1/Th17 response in IBD and psoriasis [262, 263]. Specific antibiotics (such as vancomycin) alleviate the severity of EAE by clearing proinflammatory bacteria (such as Clostridium), but long-term use may exacerbate bacterial dysbiosis [257, 264]. Intestinal microbiota intervention provides a novel therapeutic strategy for autoimmune diseases by regulating immune balance, repairing intestinal barriers, and targeting metabolic pathways. In the future, it may be possible to provide personalized therapies based on the patient's microbiota, but this still requires further research.

In summary, the current monotherapy for autoimmune diseases still focuses on broad-spectrum anti-inflammatory and molecular targeting. Cell-targeted therapy is still in the clinical trial stage, and many potential issues still need to be resolved. A summary of treatment and drug classification is provided in Table 1. The use of combination therapy is increasing [265, 266]. However, the individualized assessment of combination therapy, such as molecular typing of immune cells and biomarker detection, currently remains a major challenge.