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Abstract PAD is a prevalent and critical disease. Over the age of 50, approximately one in twenty individuals is diagnosed with PAD. The immunological system plays a significant role in plaque formation. CD4+ T-helper cells play a key role in disease onset and progression. These cells can be subtyped into various subsets based on their surface markers, functional traits, and specific cytokines. T-helper 22 cells secrete IL-22 that contributes to inflammation. Another subpopulation of CD4+ T cells called cTFH cells are identified by the expression of the surface receptor CXCR5. In this study, we aimed to evaluate of frequencies of circulating TH22 and TFH cells isolated from peripheral blood mononuclear cells in PAD patients in comparison to healthy individuals. The present study included 45 subjects, 30 of whom were PAD patients diagnosed with chronic lower limb ischemia and admitted to the Vascular Surgery Unit in Alexandria Main Hospital. They were recruited to the study to evaluate circulating follicular T helper cells and T helper-22 cell frequencies using flow cytometry. In addition, 15 healthy, non-atherosclerotic individuals served as controls. Within this research, patients were classified into 2 subgroups according to Rutherford`s classifications; group I (Stage III+ Stage IV = without trophic lesions) and group II (Stage V+ Stage VI = with trophic lesions). Results of the study indicated a statistically significant increase in TH22 cells frequencies in patients when compared to controls (p<0.001), and they increased significantly with the progression of the disease in group II (stages V and VI) when compared to patients in group I (stages III and IV) (p<0.001). The frequencies of these cells were correlated to inflammatory markers including: ESR and CRP; as well as to serum triglycerides. A decrease in frequencies of cTFH in atherosclerotic patients was found when compared to control; however, patients with higher disease stages had a statistically higher cell frequencies compared to patients in the lower stages (p=0.035* ). Therefore, from this study, we can conclude that the two cells contribute independently to disease progression. TH22 cells may play a role in the development of atherosclerosis and the progression of the disease. These cells might be considered a therapeutic target to atherosclerosis and the limitation of progression of PAD. In addition, a decrease in circulating TFH in PAD patients may reflect local accumulation in the lesions or in lymphoid tissues and we recommend further detailed studies on cTFH subsets using other markers with extension to include larger sample study, different techniques for characterization of the cells, and |