Autoimmunity

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Although CLL is characterized by progressive hypogam-maglobulinemia and defective T-cell immunity, a paradoxical event is the development of autoimmunity in some patients with this disease. The autoimmune targets are predominately hematopoietic cells, specifically mature red blood cells, platelets, or red blood cell precursors. AIHA is the most common feature and together with ITP may occur in as many as 35% of patients.5859 Much less commonly, patients may develop a lupus-like condition60 or rheumatoid arthritis.6 The mechanism by which patients develop this autoimmunity is unclear. Occasionally, such events can be severe, refractory to treatment, and lead to significant morbidity and mortality.

Autoantibodies are more common in the elderly population,61 nearly as frequent as seen with individuals with CLL; however, the incidence of AIHA is higher in patients with CLL than normal age-matched individuals. CLL is the most common cause of secondary AIHA.62 AIHA in CLL is characterized by production of polyclonal antibodies against mature red blood cells. These are "warm antibodies" and are demonstrated with the Coomb test. The autoanti-bodies are typically IgG isotype, indicating participation of activated T cells and memory cells. The prevalence of AIHA increases with advanced stage and progression of the disease.63 CLL B cells have been shown to produce Ig with low-level autoreactivity, but there is no evidence that the leukemia cells produce the autoantibodies responsible for AIHA or ITP. A significant proportion of patients (over 20%) with CLL have positive direct Coomb tests; however, not all of these patients will develop clinically significant AIHA. In addition, not all patients with active hemolysis will have a positive direct or indirect Coombs tests.

Treatment, particularly with the purine analog flu-darabine, has been associated with development of AIHA.64 65 However, randomized trials comparing flu-darabine to alkylating-agent-based therapy have not shown a significantly higher incidence of AIHA in patients receiving fludarabine. The mechanism for treatment-induced autoimmunity is likely unmasking of autoimmunity after alteration of T-lymphocyte populations.

ITP occurs in 2-5% of patients with CLL.58'63'66 ITP is more difficult to diagnose than is AIHA due to a lack of reliable diagnostic laboratory tests. Antiplatelet antibody studies are unreliable. In addition, there are other causes for thrombocytopenia patients with CLL. Specifically, thrombocytopenia may be caused by progressive bone marrow infiltration by leukemia cells with disease progression. In addition, splenomegaly that develops with disease progression may contribute to thrombocytopenia through sequestration. Despite this, it is unusual for marrow infiltration or splenomegaly to result in a platelet count less than 10,000/^L. If patients develop thrombocytopenia to this degree in the absence of cytotoxic chemotherapy, then ITP is high on the differential diagnosis.

Similarly to AIHA, ITP results from production of polyclonal antibodies of IgG isotype. Production of such antibodies implies the participation of activated T cells in this reaction and production of memory cells. Cytotoxic chemotherapy has also been reported to trigger ITP in patients with CLL. Notably, approximately one-third of patients with ITP associated with CLL also have a positive direct Coomb test.67

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