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Concept: Immune system disorders


Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions - including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity - pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.

Concepts: Immune system, Antibody, Cancer, Infectious disease, Apoptosis, Immunology, Immune system disorders, TGN1412


Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs.

Concepts: Immune system, Cell biology, Mast cell, Mastocytosis, Immune system disorders


T-cell replete post-transplant cyclophosphamide (PT-CY)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing non-engraftment or severe graft-versus-host disease (GVHD) are no longer major barriers to haploHCT. PT-CY eliminates alloreactive lymphocytes but spares CD34+ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PT-CY administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria, we identified 48 patients who developed CRS. In multivariate analysis, peripheral blood grafts were significantly associated with grade ≥2 CRS, compared to bone marrow. Grade ≥2 CRS (compared to grade <2) was not associated with differences in overall survival or non-relapse mortality. Severe CRS was associated with a statistically non-significant trend toward higher incidence of grade III-IV acute GVHD, especially in the context of peripheral blood grafts. CRS is a common complication after T-cell replete peripheral blood haploHCT, but post-transplant survival outcomes may not be affected in those with severe CRS.

Concepts: White blood cell, Bone marrow, Graft-versus-host disease, Leukemia, Hematopoietic stem cell transplantation, Thymus, Immune system disorders


This chapter describes the main features of two different diseases, Castleman Disease (CD) and Rosai-Dorfman Disease (RDD). Castleman disease (CD) is a clinical and histopathologically heterogeneous lymphoproliferative disorder that encompasses at least three distinct entities with some common overlapping morphological features: Hyaline Vascular CD (HVCD), Unicentric Plasma Cell CD and Multicentric CD. The most important feature of HVCD is the presence of abnormal germinal centers with hyaline-vascular transformation, sometimes showing multiple germinal centers within a single reactive lymphoid follicle, this outlining HVCD as a disorder of follicular dendritic cells. Unicentric and multicentric CD are, in contrast, lymphoproliferative lesions. Proinflammatory hypercytokinemia is an essential feature of multicentric CD, distinguished by a florid clinical presentation. Rosai-Dorfmann Disease is a histiocytic proliferative disorder diagnosed by the presence of tissue infiltration by S100-positive CD1a-negative histiocytes and plasma cell aggregates, often with Russell bodies. A typical, though not specific, characteristic of the disease is emperipolesis. Initially considered to be an inflammatory/reactive condition, molecular studies suggest that at least some cases of RDD could be considered as a low-grade histiocytic neoplastic process.

Concepts: Cancer, Disease, Diseases and disorders, Lymph node, Anatomical pathology, Dendritic cell, Follicular lymphoma, Immune system disorders


Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of Interleukin-6 (IL-6). Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV- and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new sub-classification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose one or more of the following three candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.

Concepts: Immune system, Inflammation, Pathology, Infection, Systemic inflammatory response syndrome, Rheumatoid arthritis, Immune system disorders, Castleman's disease


Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders.

Concepts: Immune system, Lymphocyte, Diseases and disorders, Immunodeficiency, Lymphoproliferative disorders, Immune system disorders, Primary immunodeficiency, Common variable immunodeficiency


Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder and is infrequently associated with renal complications that include amyloid A (AA) amyloidosis. Although it has been reported that patients with MCD and amyloidosis usually have a poor prognosis, recently, tocilizumab, a humanized anti-interleukin-6 receptor antibody, has emerged as an effective and specific treatment for AA amyloidosis secondary to chronic inflammatory disorders. Here we report a case of an MCD patient with secondary AA renal amyloidosis who was successfully treated with tocilizumab. The patient was initially referred to nephrology specialists because of a decline in renal function and proteinuria. Percutaneous renal biopsy revealed the presence of Congo red-positive amorphous depositions and AA protein-positive areas in glomeruli, vessel walls, and interstitium, confirming a diagnosis of renal AA amyloidosis secondary to MCD. At 1 year after starting tocilizumab treatment, a second renal biopsy showed the clearance of amyloid deposits in the interstitium. These observations suggest that tocilizumab may be an effective therapy for AA amyloidosis secondary to MCD.

Concepts: Inflammation, Nephrology, Diseases and disorders, Medical terms, Patient, Amyloidosis, Immune system disorders, Castleman's disease


The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. It is characterised by wide phenotypic variability, including congenital heart disease (CHD), immunodeficiency and scoliosis. However, little is known regarding the prevalence and characteristics of scoliosis in patients with 22q11.2DS. The objective of this study is to assess the prevalence of scoliosis, its characteristics and the association with CHD in patients with 22q11.2DS.

Concepts: Scientific method, Chromosome, Syndromes, Genetic disorders, Tetralogy of Fallot, Immune system disorders


Multicentric Castleman’s disease (MCD) is a rare kind of lymphoproliferative disorder characterized by systemic problems such as frequent fever, fatigue and weight loss with angiofollicular lymph node hyperplasia. However, unlike unicentric Castleman’s disease (UCD) with long-time survival by surgery and local radiotherapy, MCD remains poor prognosis due to no well-defined optimal treatment strategies and high risk of developing malignances especially lymphoma. We reported a case of MCD who received chemotherapy by ECHOP with unsatisfactory outcome and then oral administration with thalidomide combined with prednisone without disease progression after therapy. After 3 years, his MCD turned into multiple myeloma (MM) and accompanied by obvious response to combination of thalidomide with prednisone. Nowadays, there is no standard of therapy yet established for MCD. We successfully treated one such patient and found thalidomide based therapy may have a significant effect on MCD. We also proposed further researches with therapeutic potential about thalidomide for MCD.

Concepts: Osteoporosis, Multiple myeloma, Medicine, Cancer, Diseases and disorders, Thalidomide, Surgery, Immune system disorders


HLH occurring after HSCT is a relatively rare disease. Many conditions may mimic or trigger HLH in post-HSCT period (eg, cytokine release syndrome, engraftment syndrome, graft rejection/failure, acute graft-vs-host disease, infections systemic inflammatory response syndrome/sepsis, and thrombotic microangiopathy). Moreover, this period is usually marked by febrile illness, cytopenia, and a “cytokine storm” leading to elevation of inflammatory biomarkers like ferritin and sCD25. These parameters overlap with the diagnostic criteria for HLH. Such confounding factors make the management of post-HSCT HLH quite challenging. We illustrate this critical issue with case report of a patient who was diagnosed with HLH after allogeneic HSCT for tAML. He received MP and CsA for HLH but VP-16 was not administered due to fear of severe myelosuppression. Fortunately, he responded well to treatment and remains in remission to date. We recommend caution while using HLH-94/HLH-2004 guidelines for the diagnosis and management of post-HSCT HLH. In this article, we pinpoint these issues with a brief review of all the pediatric cases and clinical studies of post-HSCT HLH along with a critical evaluation of its various diagnostic criteria. Finally, based on the limitations of current diagnostic criteria, we suggest a need for formulating disease-specific diagnostic criteria for post-HSCT HLH.

Concepts: Inflammation, Medical terms, Diagnosis, Graft-versus-host disease, Organ transplant, Hematopoietic stem cell transplantation, Immune system disorders, TGN1412