Key protein could be a novel target for treatment of patients with B cell signaling deficiencies

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131 shares, 192 points

The rules to the kids’ game “red light, green light” are easy to follow: red always means stop, and green always means go. But now, researchers from Japan have found that a key protein involved in B cell signaling acts as both a red light to signaling in healthy cells and a green light to signaling in immune-deficient cells.

In a study published in March in Science Signaling, researchers from Tokyo Medical and Dental University (TMDU) have revealed that CD22, a crucial molecule in B cell signaling, switches from an inhibitory role to an activating role when B cell receptor (BCR) signaling is compromised due to a genetic defect that causes an immune disorder.

Contact between BCRs and foreign invaders prompts B cells to make antibodies, and CD22 inhibits BCR signaling to keep B cells from inappropriately releasing antibodies. Interestingly, previous research suggests that this inhibition is regulated by binding of CD22 to other factors expressed on the same cell. In contrast, a protein called CD45 is a main activator of BCR signaling, and defects in the gene encoding CD45 cause an immunodeficiency syndrome.

CD45 normally enhances BCR signaling. When CD45 is missing in laboratory cell lines, BCR signaling is dramatically decreased; however, signaling is not affected as severely in mice when CD45 is missing, which suggests that there is some kind of compensatory mechanism at work.”


Chizuru Akatsu, lead author on the study

To investigate the relationship between CD22 and BCR signaling restoration in the absence of CD45, the researchers disrupted the binding of all interaction partners of CD22 either continuously or for a short time and looked at the effect this had on BCR signaling.

“The results were entirely unexpected,” says Takeshi Tsubata, senior author. “Acute disruption of binding between CD22 and its ligands did not affect the restoration of BCR signaling in B cells lacking CD45, whereas continuous disruption of this binding resulted in markedly less BCR signaling recovery.”

As it turns out, the cells in which signaling was restored expressed unusually high levels of BCR, which accounted for their ability to continue functioning relatively normally. BCR signaling occurs at low levels even in the absence of stimulation by foreign antigens, and this low-level steady-state signaling is required for B cell development and survival. Because BCR is an endogenous ligand of CD22, continuous CD22 binding to its ligands facilitates inhibition of steady-state BCR signaling by CD22. If BCR signaling is compromised by a defect such as CD45 deficiency, steady-state signaling is markedly reduced by the signaling defect together with the signal inhibition by CD22; therefore, only B cells that express high levels of BCR survive. Through this mechanism, CD22 paradoxically restores BCR signaling in immune-deficient B cells.

“What is really interesting about this result is that it could point toward a way to restore immune function in patients with immune disorders involving B cell signaling deficiencies,” states Akatsu.

Given that B cells and immunoglobulins are present -; though in greatly reduced numbers -; in immunodeficient patients with defects in BCR signaling, CD22 may be a useful treatment target. Activating CD22 could help restore B cell function in patients with B cell signaling deficiencies such as X-linked agammaglobulinemia.

Source:

Journal reference:

Akatsu, C., et al. (2022) The inhibitory coreceptor CD22 restores B cell signaling by developmentally regulating Cd45−/− immunodeficient B cells. Science Signaling. doi.org/10.1126/scisignal.abf9570.

Source: News Medical


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