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1.
iScience ; 24(9): 103076, 2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34585117

RESUMEN

Systemic lupus erythematosus (SLE) is characterized by a loss of self-tolerance, systemic inflammation, and multi-organ damage. While a variety of therapeutic interventions are available, it has become clear that an early diagnosis and treatment may be key to achieve long lasting therapeutic responses and to limit irreversible organ damage. Loss of humoral tolerance including the appearance of self-reactive antibodies can be detected years before the actual onset of the clinical autoimmune disease, representing a potential early point of intervention. Not much is known, however, about how and to what extent this pre-phase of disease impacts the onset and development of subsequent autoimmunity. By targeting the B cell compartment in the pre-disease phase of a spontaneous mouse model of SLE we now show, that resetting the humoral immune system during the clinically unapparent phase of the disease globally alters immune homeostasis delaying the downstream development of systemic autoimmunity.

2.
Cell Rep ; 29(10): 3033-3046.e4, 2019 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-31801071

RESUMEN

Cytotoxic immunoglobulin G antibodies are an essential component of therapeutic approaches aimed at depleting self-reactive or malignant cells. More recent evidence suggests that the tissue in which the target cell resides influences the underlying molecular and cellular pathways responsible for cytotoxic antibody activity. By studying cytotoxic IgG activity directed against natural killer cells in primary and secondary immunological organs, we show that distinct organ-specific effector pathways are responsible for target cell depletion. While in the bone marrow, the classical complement pathway and the high-affinity Fcγ-receptor I expressed on organ-resident macrophages were both involved in removing opsonized target cells; in the spleen and blood, all activating FcγRs but not the classical complement pathway were critical for target cell killing. Our study suggests that future strategies aimed at optimizing overall cytotoxic antibody activity may need to consider organ-specific pathways to achieve a maximal therapeutic effect.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Animales , Femenino , Inmunoglobulina G/inmunología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de IgG/inmunología , Bazo/inmunología
3.
Exp Dermatol ; 26(8): 691-696, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-27512946

RESUMEN

IgG antibodies are potent inducers of proinflammatory responses by cross-linking Fc receptors on innate immune effector cells resulting in tissue injury. The recently discovered enzymes endoglycosidase S (EndoS) and IgG-degrading enzyme (IdeS) of Streptococcus pyogenes are able to modulate the interaction between IgG antibodies and the Fc receptors, by hydrolysis of the glycan associated with the heavy chain of the IgG molecule (EndoS), or cleavage in the hinge region of the heavy IgG chain (IdeS). In this work, we investigated their ability to inhibit damage mediated by skin-bound antibodies in vivo in two different experimental models, the Arthus reaction, and epidermolysis bullosa acquisita, an autoimmune blistering skin disease associated with autoantibodies against type VII collagen. We demonstrate that both enzymes efficiently interfere with IgG-mediated proinflammatory processes, offering a great asset to specifically target pathological IgG antibodies in the skin and holding great promise for future applications in human therapy.


Asunto(s)
Reacción de Arthus/prevención & control , Proteínas Bacterianas/uso terapéutico , Epidermólisis Ampollosa Adquirida/prevención & control , Glicósido Hidrolasas/uso terapéutico , Animales , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/farmacología , Colágeno Tipo VII/inmunología , Evaluación Preclínica de Medicamentos , Femenino , Glicósido Hidrolasas/metabolismo , Glicósido Hidrolasas/farmacología , Inmunoglobulina G/metabolismo , Ratones Endogámicos C57BL
4.
Immunity ; 35(6): 932-44, 2011 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-22169040

RESUMEN

Immunoglobulin G (IgG) antibodies confer protection against pathogenic microorganisms, serve as therapeutics in tumor therapy, and are involved in destruction of healthy tissues during autoimmune diseases. Understanding the molecular pathways and effector cell types involved in antibody-mediated effector functions is a prerequisite to modulate these activities. In this study we used two independent model systems to identify innate immune effector cells required for IgG activity in vivo. We first defined the precise repertoire of receptors for the IgG Fc fragment (FcγR) on innate immune effector cells in the blood and on tissue-resident macrophage populations. Despite expression of relevant activating FcγRs on various phagocyte populations, our data indicate that the majority of these cell types are dispensable for IgG activity in vivo. In contrast, IgG-dependent effector functions were selectively impaired in animals lacking the CX(3)CR1(hi)Ly6C(lo)CD11c(int) monocyte subset, which expressed the full set of FcγRs required for IgG activity.


Asunto(s)
Inmunoglobulina G/fisiología , Monocitos/inmunología , Animales , Linfocitos B/metabolismo , Plaquetas/metabolismo , Modelos Animales de Enfermedad , Femenino , Granulocitos/inmunología , Inmunidad Innata , Fragmentos Fc de Inmunoglobulinas/inmunología , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Depleción Linfocítica , Macrófagos/inmunología , Macrófagos/metabolismo , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/clasificación , Monocitos/metabolismo , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/metabolismo , Receptores de IgG/inmunología , Receptores de IgG/metabolismo
5.
Proc Natl Acad Sci U S A ; 107(45): 19396-401, 2010 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-20974962

RESUMEN

Cellular Fcγ receptors are essential for IgG-dependent effector functions in vivo. There is convincing evidence that selective activating Fcγ receptors are responsible for the activity of individual IgG subclasses. Thus, IgG1 activity is absent in FcγRIII-deficient mice, and several studies suggest that the activity of the most potent IgG subclasses, IgG2a and IgG2b, might be dependent on either individual or a combination of activating FcγRs. To study the role of individual activating FcγRs for IgG subclass activity, we generated an FcγRIV-deficient mouse and showed that a variety of IgG2a- and IgG2b-dependent effector functions are impaired in the absence of this activating Fc receptor in models of autoimmunity and antibody-dependent cellular cytotoxicity.


Asunto(s)
Inmunoglobulina G/inmunología , Receptores de IgG/deficiencia , Animales , Citotoxicidad Celular Dependiente de Anticuerpos , Autoinmunidad , Ratones , Ratones Noqueados , Modelos Animales , Receptores de IgG/fisiología
6.
Proc Natl Acad Sci U S A ; 105(39): 15005-9, 2008 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-18815375

RESUMEN

IgG antibodies are potent inducers of proinflammatory responses. During autoimmune diseases such as arthritis and systemic lupus erythematosus, IgG autoantibodies are responsible for the chronic inflammation and destruction of healthy tissues by cross-linking Fc receptors on innate immune effector cells. The sugar moiety attached to the asparagine-297 residue in the constant domain of the antibody is critical for the overall structure and function of the molecule. Removal of this sugar domain leads to the loss of the proinflammatory activity, suggesting that in vivo modulation of antibody glycosylation might be a strategy to interfere with autoimmune processes. In this work, we investigated whether removal of the majority of the IgG-associated sugar domain by endoglycosidase S (EndoS) from Streptococcus pyogenes is able to interfere with autoimmune inflammation. We demonstrate that EndoS injection efficiently removes the IgG-associated sugar domain in vivo and interferes with autoantibody-mediated proinflammatory processes in a variety of autoimmune models. Importantly, however, we observed a differential impact of EndoS-mediated sugar side chain hydrolysis on IgG activity depending on the individual IgG subclass.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Autoanticuerpos/efectos de los fármacos , Enfermedades Autoinmunes/tratamiento farmacológico , Proteínas Bacterianas/administración & dosificación , Glicósido Hidrolasas/administración & dosificación , Inmunoglobulina G/efectos de los fármacos , Animales , Artritis Experimental/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Glicosilación , Hidrólisis , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inyecciones Intraarteriales , Ratones , Ratones Endogámicos C57BL , Polisacáridos/metabolismo
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