Editorial: Are the inflammatory bowel diseases immune complex diseases?
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Antigen-Antibody Complex↗
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Von Willebrand factor and von Willebrand's disease: a complex protein and a complex disease.
Von Willebrand factor is a complex protein which is important in several ways for normal hemostasis. Von Willebrand's disease results when there is either a quantitative or qualitative disorder of von Willebrand factor. In this review, the structure and function of von Willebrand factor are discussed. Additionally, the current laboratory and clinical classification of von Willebrand's disease and closely related variants are outlined.
Factor VIII↗
Shared etiology of Mendelian and complex disease supports drug discovery.
BACKGROUND: Drugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease. METHODS: In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations. RESULTS: Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated. CONCLUSIONS: Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.
Humans↗
[Immune complex diseases].
Immune complex diseases (ICD) include different diseases of infectious and noninfectious origin in the pathogenesis of which the leading role belongs to immune complexes circulating in the blood stream. Three variants of the ICD course are distinguished: fulminant, acute, and chronic. The main morphological manifestation of ICD is vasculitis (in the fulminant course--microangiothrombopathy) and its consequences in the form of various circulation disorders. Renal glomeruli are frequently involved (glomerulonephritis). Immunopathologic reactions in the form of hypersensitivity reaction or inhibition of immune response are important in ICD.
Arterioles↗
[Kawasaki disease as immune complex disease].
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Humans↗
[Autoimmune diseases and immune complex diseases].
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Antigen-Antibody Complex↗
Chemical dependency: a complex disease and a complex problem.
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Humans↗
[Immunologic and allergic lung diseases. 2. Endogenous and exogenous immune complex diseases].
For the respiratory tract immunologic reactions of type I and type III according to Coombs and Gell are most important. The classical example for type-I-reaction is extrinsic (= "allergic") asthma. Mechanisms of sensitzation, of mediator release out of mast cells and of immunotherapy by specific hyposensitization are summarized. Immunologic type-III-reactions may lead to immune complex diseases of the lung. There are two different pathways: In the several forms of extrinsic alveolitis the interstitial lung tissue is involved, whereas the intrinsic forms of immune complex diseases mainly result in lung vasculitis. The diagnostic and therapeutical essentials of immunologic and allergic lung disease are discussed in detail.
Adrenal Cortex Hormones↗
Intravenous gamma-globulin therapy in systemic lupus erythematosus and immune complex disease.
Immune complexes (ICs) are felt to be of primary pathological importance in the mediation of many human glomerular diseases. This is based on the demonstration of Ig and C' in renal cortex tissue of affected individuals. Systemic lupus erythematosus (SLE) is a prototype IC disease where ICs have been demonstrated in target tissues. Moreover, glomerulonephritis (GN) is a common feature of many autoimmune and infectious diseases associated with IC generation. Current therapeutic alternatives are restricted to immunosuppressive agents. Tomino et al. (Clin. Exp. Immunol. 58, 42, 1984) demonstrated that glomerular IC deposits could be solubilized with HGG. Palla et al. (Clin. Nephrol. 26, 314, 1986) treated four membranous nephritis patients with IVGG and had dramatic resolution of proteinuria in three of them. Gaedlicke et al. (Blut 48, 387, 1984) reported improvement in vasculitis in one of two patients treated with IVGG. We have experienced exacerbation of GN with IVGG therapy in two SLE patients. IVGG is useful in treating the common variable immunodeficiency that occurs in some SLE patients and in treating the immunodeficiency associated with florid nephrotic syndrome. IVGG given to one patient with Henoch-Schönlein purpura resulted in the onset of gross hematuria. In sum, IVGG may be useful in treating specific IC renal diseases by solubilization of circulating or in situ ICs but definitive proof is lacking. In other situations, IVGG may exacerbate the glomerulonephritis, possibly through enhanced IC formation. Furthermore, IVGG may induce modulation of immune responses by induction of auto-anti-idiotypic immunity.
Antibodies, Anti-Idiotypic↗
Biological Foundation Models for Complex Disease Research and Clinical Translation.
Complex diseases, including cancer, rare genetic disorders, neurodevelopmental and psychiatric conditions, and neurodegenerative diseases, arise from interactions among genetic variation, gene regulation, and cellular states that are difficult to capture using a single data type or biological scale. Biological foundation models address this challenge by treating nucleotides and genes as tokens and learning representations that can be transferred to downstream biomedical and clinical tasks. In this review, we examine two major model classes, genomic sequence foundation models and cell foundation models, and compare their tokenization strategies, model architectures, pretraining objectives, and adaptation methods. We summarize their emerging applications in regulatory variant interpretation, disease-associated cell-state analysis, drug-response prediction, and therapeutic target discovery across complex diseases. We distinguish applications supported by experimental or retrospective validation from those that remain primarily computational or conceptual. We further discuss key challenges to clinical translation, including multimodal data integration, model interpretability, benchmarking, patient-specific prediction, and privacy protection. We highlight future opportunities to integrate biological foundation models with emerging frameworks of medical digital twins, agentic AI, and federated learning. By linking model design to translational goals, this review provides a practical framework for evaluating biological foundation models and their readiness for complex disease research and clinical use.
biological foundation model↗
Virus-induced immune complex disease: identification of specific viral antigens and antibodies deposited in complexes during chronic lymphocytic choriomeningitis virus infection.
Structural proteins of LCMV were identified and their role in the immune complex glomerulonephritis of LCMV carrier mice was examined. Purified LCMV contained three major polypeptides, a single nonglycosylated nucleoprotein with an estimated m.w. of 63,000, and two surface glycoproteins of 54,000 and 35,000. Deposition of nucleoprotein antigen in the glomeruli of LCMV carrier mice of several strains was demonstrated by immunofluorescent staining with a monospecific antibody. In addition, Ig eluted from kidneys of three strains of LCMV carrier mice was shown by immune precipitation to react against all of major viral polypeptides of LCMV. Antibody from normal mice, and from mice with immune complex disease unrelated to LCMV did not show deposition of LCMV antigen in glomeruli, and Ig eluted from the kidneys of these mice did not react against LCMV antigens. Hence, mice infected at birth with LCMV and persistently infected throughout their life make antibodies to all the known structural polypeptides of the virus.
Animals↗
[Virus disease complexes: transmissible pathological entities in invertebrates].
Virus disease complexes of Galleria mellonella L. due respectively to a Parvovirus with a Baculovirus and a Parovirus with an Iridovirus have been transmitted to healthy larvae by ingestion of corpses of larvae affected by these disease complexes. The histological and cytological injuries observed are identical to those noted during the study of the initial complexes.
Adipose Tissue↗
Locus-specific stratification and prioritization unveil genetic risk mechanism underlying complex diseases.
Although genome-wide association studies have identified thousands of disease-associated loci, the mechanistic understanding and drug target discovery remain challenging, particularly for complex diseases. The multi-signal architecture of complex diseases complicates the interpretation of genetic contributions. To address this challenge, we develop an approach comprising locus-specific stratification (LSS) and gene regulatory prioritization score (GRPS), which uniquely considers multi-signals during fine-mapping and target gene identification. LSS significantly enhances the interpretability of genetic risk associated with complex diseases. For loci associated with serum urate levels, the method identifies candidate causal genes in 34.43% of loci, surpassing the performance of other methods by 5.47% to 25.14%. GRPS considers the regulatory network of LSS-variants comprehensively and successfully nominates under-explored drug targets for hyperuricemia with high confidence such as SLC17A4, which is further validated using epigenetic activation and phenotypic assays. This study introduces an approach to efficiently and comprehensively address the multi-signal challenges in complex diseases.
Humans↗
Pityriasis lichenoides--an immune complex disease.
Circulating immune complexes have been detected in patients with pityriasis lichenoides during disease activity when IgM and C3 have been observed in dermal vessels on direct immunofluorescence of fresh lesions. This implies that pityriasis lichenoides is an immune complex disorder and that deposited complexes play a part in the pathogenesis of the condition. There is a characteristic pattern of immunofluorescence which may be a diagnostic aid.
Adolescent↗
Pulmonary immune effector cells: II. Antigen-specific blastogenic responsiveness of lymphocyte populations during pulmonary immune complex disease in guinea pigs.
A guinea pig pulmonary immune complex disease was used to evaluate local antigen (ovalbumin)-specific lymphoproliferative responses in lung tissue, bronchoalveolar spaces, and hilar lymph nodes (HLN) at various time intervals after challenge. The responses of lung tissue and bronchoalveolar lymphocytes appear to be mediated by T cells, whereas the response of HLN lymphocytes was mediated by B and/or T cells, depending on the stage of the disease. The blastogenic response of HLN lymphocytes to concanavalin A was much greater than that observed in lung tissue or bronchoalveolar lymphocyte preparations, even after the removal of adherent cells, suggesting a possible inherent difference between these cell populations in their response to mitogen. This study demonstrates that lung tissue, bronchoalveolar, and HLN lymphocytes are not only capable of responding blastogenically to specific antigen, but that this responsiveness varies throughout the course of the disease. The lymphoproliferative responses and concurrent changes in the proportion of pulmonary immune effector cells are discussed in relation to cellular immunoregulation during the in vivo progression of this pulmonary immune complex disease.
Animals↗
Are rare variants responsible for susceptibility to complex diseases?
Little is known about the nature of genetic variation underlying complex diseases in humans. One popular view proposes that mapping efforts should focus on identification of susceptibility mutations that are relatively old and at high frequency. It is generally assumed-at least for modeling purposes-that selection against complex disease mutations is so weak that it can be ignored. In this article, I propose an explicit model for the evolution of complex disease loci, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations. I show that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease. Instead, it seems likely that the bulk of genetic variance underlying diseases is due to loci where susceptibility mutations are mildly deleterious and where there is a high overall mutation rate to the susceptible class. At such loci, the total frequency of susceptibility mutations may be quite high, but there is likely to be extensive allelic heterogeneity at many of these loci. I discuss some practical implications of these results for gene mapping efforts.
Alleles↗
Is primary biliary cirrhosis an immune complex disease?
Large immune complexes are present in the circulation of patients with primary biliary cirrhosis and result in the activation of complement by the classical pathway. Such large complexes are capable of producing tissue damage. The granulomatous lesions surrounding the small bile-ducts within the liver of patients with primary biliary cirrhosis and the vasculitis, rheumatoid arthritis, and associated lesions are all compatible with immune complex injury. It is postulated that such large complexes could be formed in the vicinity of the bile-ducts by an antigen absorbed from the bile or biliary epithelium. Complexes reaching the systemic circulation might be responsible for the associated extra-hepatic diseases.
Antibody Formation↗
Virus-associated immunopathology: animal models and implications for human disease. 1. Effects of viruses on the immune system, immune-complex diseases, and antibody-mediated immunologic injury.
The tissue damage caused by virus infection has been traditionally explained by the ability of viruses to multiply in cells and thereby injure or destroy them. Recent evidence suggests, however, that lesions may also be caused by the host's immune response to viral antigens and that the immune system itself may be perturbed by some viruses. This memorandum reviews recent developments in viral immunopathology, with special reference to animal model systems, and indicates the possible relevance of the new concepts and techniques for certain diseases of man. Certain viruses, notably the leukaemia viruses and some of those causing persistent infections, depress the host's ability to mount an antibody response to antigens, while other viruses may enhance the antibody response. Cell-mediated immunity may also be depressed. Another immunopathological manifestation of virus infection is immune-complex disease. When viruses or their antigens persist in the circulation they combine with specific antibody, and the resulting complexes lodge in various sites, especially the kidney. Further combination with complement leads to the release of tissue-damaging substances. A third condition associated with virus infection is antibody-mediated immunologic injury. Both oncogenic and non-oncogenic viruses frequently induce new antigens on the surface of the cells they invade. When antibody attaches to these antigens in the presence of complement, the cells are destroyed.
Animals↗