Reduced Blood Leukocyte and Neutrophil Numbers in the Pathogenesis of Type 1 Diabetes

Abstract

Very little is known about the role of the innate immune system in the course of human type 1 diabetes. Here we investigated neutrophil numbers along with other leukocyte populations in patients at diagnosis of type 1 diabetes and during prediabetes. Complete and differential blood counts were analyzed from 107 adult patients with newly diagnosed type 1 diabetes, 21 children with persistent islet autoantibodies and a family history of type 1 diabetes, and 1 238 age and gender matched control subjects, all individuals without any signs of acute infection.Adult patients with newly diagnosed type 1 diabetes had significantly lower total WBC (p<1×10⁻⁶), neutrophil (p<1×10⁻⁶), basophil (p<1×10⁻⁶), monocyte (p=4×10⁻⁶) and lymphocyte (p<1×10⁻⁶) counts compared to control subjects. Erythrocyte, eosinophil and platelet counts did not differ between groups. Similarly, children with persistent islet autoantibodies had decreased WBC (p=0.001), neutrophils (p=0.003), and lymphocytes (p=0.006) in comparison to control children. Our findings demonstrate a perturbation of leukocyte homeostasis at and prior to onset of type 1 diabetes suggesting a general involvement of the innate immune system in the pathogenesis of type 1 diabetes.

Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis Are Closely Associated With β-Cell Autoimmunity in Patients With Type 1 Diabetes

“…No significant differences in C-reactive protein were found among these groups (Table 1). Consistent with previous reports (10,11), circulating neutrophils were moderately reduced in T1D patients diagnosed within 1 year compared with the healthy control subjects (median 2. 6 /mL; P , 0.05), but not in T1D patients with a disease duration of .1 and ,5 years or with duration .5 years (Table 1).…”

“…A number of other immune cells, including dendritic cells, macrophages, B cells, and neutrophils, are also implicated in the development of insulitis in T1D (8,9). Neutrophils, which are the most abundant (40-75%) type of white blood cells, have recently been implicated in the onset and progression of T1D (10,11). The primary functions of neutrophils are to eliminate extracellular pathogens by multiple strategies, including phagocytosis, degranulation to release lytic enzymes, and neutrophil extracellular traps (NETs) that are formed through a unique cell death process clearly differentiated from apoptosis and necrosis, termed "NETosis" (12)(13)(14).…”

NETosis-associated serum biomarkers are reduced in type 1 diabetes in association with neutrophil count

“…However, as these markers are products of neutrophils, we thought the findings could be related to a reduction in neutrophil numbers, which has been reported previously by multiple groups [7,8]. Consistent with these reports, the RO T1D subgroup had reduced numbers of neutrophils compared to controls (3Á2 6 0Á9 3 10 3 /ll versus 4Á4 6 1Á8 3 10 3 /ll; mean 6 s.d.)…”

“…In contrast to our original hypothesis, the primary finding was that of reduced circulating PR3 and NE levels in those with recently diagnosed T1D, reflecting a mild neutropenia occurring consistent with previous reports [7,8]. The reason for these neutrophil reductions is still not clear.…”

“…For instance, the frequency of natural killer (NK) T cells and a subpopulation of myeloid dendritic cells has been reported to correlate with C-peptide loss [5,6]. In addition, multiple laboratories have reported a reduction in the number of circulating neutrophils near the time of T1D diagnosis as well as prior to onset [7,8]. Somewhat paradoxically considering these findings, a recent study has raised a significant amount of interest in the field, showing extremely high levels of neutrophil-derived enzymes in the serum of newly diagnosed T1D patients [9].…”