The majority of patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) have antineu-trophil cytoplasmic antibodies (ANCA) in their serum. This is particularly true of patients with “disseminated” disease, the great majority of whom are ANCA positive. WG and MPA are often termed “ANCA-associated vasculitides” (AAV), even though not all patients with these conditions have ANCA. The Churg—Strauss syndrome, another disorder classified as an AAV, is discussed in Chap. 23. Multiple antibodies may lead to positive immunofluores-cence testing for ANCA in either perinuclear (P-ANCA) or cytoplasmic (C-ANCA) patterns. However, only antibodies to myeloperoxidase (MPO) and proteinase-3 (PR3) are associated with the A AV. Antibodies directed against PR3 and MPO are termed PR3-ANCA and MPO-ANCA, respectively. WG may be associated with destructive upper respiratory tract disease, including saddle-nose deformity, erosive sinusitis, and subglottic stenosis. A host of ocular lesions may occur in the A AV, including episcleritis, scleritis, peripheral ulcerative keratitis, and orbital pseudotumor. Most of these lesions are more common in WG than in MPA. Lung disease in the AAV ranges from nodular lesions with a tendency to cavitate (in WG), to interstitial lung disease (MPA), and to alveolar hemorrhage (both WG and MPA). Segmental, necrotizing glomerulonephritis commonly accompanies the AAV. Because of the paucity of immunoreactants such as immunoglobulins and complement components in kidney biopsies relative to the biopsies from patients with immune complex-mediated glomerulonephritis, the glomerulonephritis of the A AV is termed “pauci-immune.”

/pdf/anca-associated-vasculitis-3kwhbyor9l.pdf

ANCA-associated vasculitis.

The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.

https://www.nefro.cl/DOCS/evento1/papers/The%20immune%20system%20and%20kidney.%20nature%20reviews.pdf

The immune system and kidney disease: basic concepts and clinical implications

In addition to physical barriers, neutrophils are considered a part of the first line of immune defense. They can be found in the bloodstream, with a lifespan of 6-8 hours, and in tissue, where they can last up to seven days. The mechanisms that neutrophils utilize for host defense are phagocytosis, degranulation, cytokine production and, the most recently described, neutrophil extracellular trap (NET) production. NETs are DNA structures released due to chromatin decondensation and spreading, and they thus occupy 3-5 times the volume of condensed chromatin. Several proteins adhere to NETs, including histones and over 30 components of primary and secondary granules, among them components with bactericidal activity such as elastase, myeloperoxidase, cathepsin G, lactoferrin, pentraxin 3, gelatinase, proteinase 3, LL-37, peptidoglycan-binding proteins and others with bactericidal activity able to destroy virulence factors. Three models for NETosis are known to date. a) Suicidal NETosis, with a duration of 2-4 hours, is the best described model. b) In vital NETosis with nuclear DNA release, neutrophils release NETs without exhibiting loss of nuclear or plasma membrane within 5-60 minutes, and it is independent of ROS and the Raf/MERK/ERK pathway. c). The final type is Vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and LPS. Recent research has revealed neutrophils as more sophisticated immune cells that are able to precisely regulate their granular enzymes release by ion fluxes and can release immunomodulatory cytokines and chemokines that interact with various components of the immune system. Therefore, they can play a key role in autoimmunity and in autoinflammatory and metabolic diseases. In this review, we intend to show the two roles played by neutrophils: as a first line of defense against microorganisms and as a contributor to the pathogenesis of various illnesses, such as autoimmune, autoinflammatory and metabolic diseases.

/pdf/neutrophil-extracellular-traps-and-its-implications-in-53uvfva0xl.pdf

Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview.

A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

/pdf/molecular-mimicry-as-a-mechanism-of-autoimmune-disease-3vi5hitile.pdf

Molecular Mimicry as a Mechanism of Autoimmune Disease

Antineutrophil cytoplasmic autoantibodies (ANCAs) are the probable cause of a distinct form of vasculitis that can be accompanied by necrotizing granulomatosis. Clinical and experimental evidence supports a pathogenesis that is driven by ANCA-induced activation of neutrophils and monocytes, producing destructive necrotizing vascular and extravascular inflammation. Pathogenic ANCAs can originate from precursor natural autoantibodies. Pathogenic transformation might be initiated by commensal or pathogenic microbes, legal or illegal drugs, exogenous or endogenous autoantigen complementary peptides, or dysregulated autoantigen expression. The ANCA autoimmune response is facilitated by insufficient T-cell and B-cell regulation. A putative pathogenic mechanism for vascular inflammation begins with ANCA-induced activation of primed neutrophils and monocytes leading to activation of the alternative complement pathway, which sets in motion an inflammatory amplification loop in the vessel wall that attracts and activates neutrophils with resultant respiratory burst, degranulation, extrusion of neutrophil extracellular traps, apoptosis and necrosis. The pathogenesis of extravascular granulomatosis is less clear, but a feasible scenario proposes that a prodromal infectious or allergic condition positions primed neutrophils in extravascular tissue in which they can be activated by ANCAs in interstitial fluid to produce extravascular necrotizing injury that would initiate an innate granulomatous inflammatory response to wall off the necrotic debris.

Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease

Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.

http://cmgm.stanford.edu/biochem/biochem230/nominations/FALL2008NOMINATIONS/Molecular%20mimicry%20in%20pauci-immune%20focal%20necrotizing%20glomerulonephritis.pdf

Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis


 Background: The Advanced Breast Cancer (ABC) program at The University of Texas MD Anderson Cancer Center was created by metastatic breast cancer (MBC) patients for MBC patients. The ABC Program seeks to improve quantity and quality of life for patients living with MBC. MD Anderson actively treats 2,076 patients living with MBC. ABC program patient advocates voiced the need to increase MBC patients’ access to internal medicine services coordinated with oncology care.
 Significance: Previous literature suggests patients living with MBC have difficulty receiving oncology coordinated internal medicine services due to their terminal diagnosis and indefinite prescription of anti-cancer treatment. Comorbidities in this setting are known to be associated with inferior outcomes. ABC Program patient advocates reported various challenges seeking care from community based medical professionals including, timely awareness of their local provider on the status of their cancer. Other challenges included the lack of familiarity of some providers with novel MBC cancer treatment, side effects, and interactions of their cancer treatment with non-cancer conditions and treatment. Therefore, with the increasing life expectancy of MBC patients, there is a growing realization of the importance of managing the medical comorbidities in coordination with the MBC patient’s cancer treatment.
 Purpose: To increase access and coordinate internal medicine services for MBC patients with medical comorbidities.
 Interventions: In partnership with ABC Program patient advocates, the Linking Internal Medicine and Metastatic Breast cancer for Success (LIMBS) clinic was created in February 2021. The LIMBS clinic aimed to bridge the gap in lack of oncology coordinated internal medicine service for MBC patients.
 Evaluation: Breast Medical Oncology providers requested LIMBS clinic consults for 108 patients for comorbidity management since the clinic inception. This is a 44% increase in internal medicine consultations prior to LIMBS clinic creation (60 vs 108). The LIMBS clinic consults resulted in 474 follow up visits. Compared to MBC patients at MD Anderson, LIMBS patients were more likely to be African American (20% vs 13%) and were more likely to be older (59 years vs 57 years). Gender, marital status, and clinical trial enrollment did not differ between LIMBS patients and MBC patients. LIMBS patients had significantly higher rates of hypertension (46% vs 19%), Type II DM (19% vs 6%), hyperlipidemia (13% vs 10%), and hypothyroidism (13% vs 6%) compared to MBC patients in general. LIMBS patients had lower rates of anxiety (8% vs 11%) and depression (2% vs 7%) when compared to the MBC patients in general. The top 10 comorbidities for all MBC patients versus LIMBS patients are listed in Table 1.
 Discussion: It is feasible to build and integrate internal medicine with breast medical oncology services for patients with metastatic breast cancer. Future research should focus on exploring, describing, and meeting the internal medicine needs of MBC patients. Future initiatives are needed to bridge the gap in care for oncology coordinated internal medicine services between community and tertiary care centers.
 Table 1. Top 10 Comorbidities of all MBC patients versus LIMBS clinic patients Note. This table demonstrates the top 10 comorbidities for MBC population and the LIMBS population.
 Citation Format: Abbey Kaler, Akshara Singareeka Raghavendra, Ginny T. Kirklin, Dawn Cunningham, Ellen Manzullo, Debu Tripathy, Zayd Razouki. Linking Internal Medicine Care to Metastatic Breast Cancer Patients for Success: LIMBS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-22.

Abstract P4-03-22: Linking Internal Medicine Care to Metastatic Breast Cancer Patients for Success: LIMBS

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Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis

Abstract P4-03-22: Linking Internal Medicine Care to Metastatic Breast Cancer Patients for Success: LIMBS