**2.1. Anti-CD20 antibody therapy in type 1 diabetes**

B cells are immune cells that produce antibodies when stimulated by exogenous or endoge‐ nous antigens. Several autoimmune diseases are associated with self-reactive B cells such as systemic lupus erythematosus and idiopathic thrombocytopenia. Reports have shown that depletion of B cells ameliorates such autoimmune conditions [7-9]. CD20 is highly expressed on the surface of mature B cells and is the B cell-specific marker. Thus, anti-CD20 antibody has been employed for the *in vivo* depletion of B cells. The FDA-approved drug, anti-human CD20, Rituximab has been used clinically for CD20+ B cell lymphoma for over a decade and largely improved the survival of patients with B cell lymphoma. Recently, anti-CD20 thera‐ py was tested in several clinical trials for the treatment of B cell-mediated autoimmune dis‐ eases and demonstrated promising efficacy including a clinical study for the new onset T1D patients [10]. We will get into details on how anti-CD20 therapy works, its efficacy in treat‐ ing T1D, the potential adverse effects as well as the issues to be solved in the future.

#### *2.1.1. The mechanisms of action of anti-CD20 therapy*

It is generally believed that the effect of anti-CD20 therapy results from the depletion of B cells by the anti-CD20 antibodies *in vivo*. However, the mechanism of action of anti-CD20 therapy is largely beyond B cell depletion. Several mechanisms have been proposed con‐ cerning the action of anti-CD20 therapy.

### *2.1.1.1. Complement activation in anti-CD20 therapy*

Complement activation by binding the Fc fragment of the antibody leads to cell lysis, or named complement-dependent cytoxicity (CDC). Complement-dependent cell lysis is con‐ trolled by the degree of complement activation and regulated by a series of complement in‐ hibitory proteins, such as CD35, the complement receptor type 1; CD46, the membrane cofactor protein; CD55, the decay accelerating factor; and CD59, the membrane inhibitor of reactive lysis. It appears that the ability of CD20 to move into lipid rafts is needed for CDC to occur [11]. Some protein kinase pathways are also involved in regulating CDC activity, e.g. the activation of PKC, PKA and MEK is associated with B cell resistance to CDC [12]. Furthermore, complement activation has other effects besides cell lysis, such as depositing C3, C3b and additional CD3b breakdown products on the cell surface [13].
