Fig. 5.30 ). The disorder is often, but not always, associated with elevated serum IgG4 concentrations. Increased numbers of IgG4-producing plasma cells in tissue are a sine qua non of this disorder. IgG4-related disease has now been described in virtually every organ system, including the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin. Many conditions long viewed as disorders of single organs are now part of the IgG4-RD spectrum. These include Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands),
Riedel thyroiditis, idiopathic retroperitoneal fibrosis, autoimmune pancreatitis, and inflammatory pseudotumors of the orbit, lungs, and kidneys, to name a few. The disease most often affects middle-aged and older men.
The pathogenesis of this condition is not understood, and although IgG4 production in lesions is a hallmark of the disease, it is not known if this antibody type contributes to the pathology. The key role of B cells is supported by clinical trials in which depletion of B cells by anti–B-cell reagents such as rituximab provided clinical benefit.
A major barrier to transplantation is the process of rejection, in which the recipient’s immune system recognizes the graft as foreign and attacks it. The key to successful transplantation has been the development of therapies that prevent or minimize rejection. Transplant rejection is discussed here because it involves several of the immunologic reactions that underlie immune-mediated inflammatory diseases.
Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and destroy the grafts. We next discuss how this occurs.
Recognition of Graft Alloantigens
The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in HLA alleles. Grafts exchanged between individuals of the same species are called allografts. Because HLA genes are highly polymorphic, there are always some differences between individuals (except, of course, identical twins). Following transplantation, the recipient’s T cells recognize donor antigens from the graft (the allogeneic antigens, or alloantigens) by two pathways. The graft antigens are either presented directly to recipient T cells by graft APCs, or the graft antigens are picked up by host APCs, processed (like any other foreign antigen), and presented to host T cells. These are called the direct and indirect pathways of recognition of alloantigens. Both lead to the activation of CD8+ T cells, which develop into CTLs, and CD4+ T cells, which become cytokine-producing effector cells, mainly TH1 cells. We do not know the relative importance of these pathways in the rejection of allografts. The direct pathway may be most important for CTL-mediated acute rejection, and the indirect pathway may play a greater role in chronic rejection, described later.
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A 1.0 cm B C D
Fig. 5.30 IgG4-relateddisease:representativelesions.(A)Bileductshowingsclerosingcholangitis.(B)Scleroticareaofthebileductwithstoriformfibrosis.(C)Submandibularglandwithinfiltratesoflymphocytesandplasmacellsandwhorlsoffibrosis.(D)SectionofaninvolvedlacrimalglandstainedwithanantibodyagainstIgG4,showinglargenumbersofIgG4-producingplasmacells.(From Kamisawa T,Zen Y,Pillai S,et al:IgG4-related disease. Lancet385:1460, 2015.)