Larry,
With the proliferation of ultra-small, smooth and stone reliable centerfire deep cover handguns out there, it's difficult for me to imagine a situation where a person would be better off going armed with a .22.
An NAA Guardian or Seecamp .32 ACP are smaller than just about any .22 I can think of; advancements in .32 ACP ammo have put this cartridge well ahead of where it was just twenty years ago.
Colt's Mustang and Pony Pocketlites are a bit larger externally than the .32s, but are actually a couple of ounces lighter; both are chambered for the .380 ACP round, which also has seen considerable technological development in the fairly recent past.
Personally, I would (and do!) trust either of the above much more than I would any .22 rimfire handgun for defensive purposes.
Regards,
----Mac