1. Penetration- .22LR is more than capable of reliably penetrating calibrated ballistics gel to and exceeding the FBI recommended 12", at defensive ranges from handgun-length barrels. Tested by Brass Fetcher.
2. Chambering- .22LR is no more or less reliable to feed in automatic firearms than any other cartridge; the fact that it is rimmed is accounted for in firearms design. Feed reliability is therefore a factor of the firearms manufacturer's design and quality, not an inherent quality of the cartridge. It's down to the firearm in question, not the cartridge it's chambered for. This is true of all semiauto firearms, not just ones chambered for rimfire ammunition.
3. Ignition Reliability-- This oft-cited reason that rimfire cartridges are unacceptable for self-defense, although it may have been valid at one point in history, simply does not bear out in reality in the present day. Primer failures in even range/target grade "plinking" ammo from manufacturers such as Federal, Remington, and Winchester are rare; it is not uncommon to go through many thousands of rounds of such ammo without a single primer failure, and higher-quality 'match' grade ammunition is ever more reliable. The disconnect between report and reality in this enduring myth has led to suspicion that those who are supplying this anecdotal evidence of .22LR ignition unreliability are using poorly-made or poorly-maintained firearms light-striking the primer, or simply using old or very poor quality ammunition... which would lead to ignition reliability problems in any caliber or cartridge, centerfire included.
Conclusion: .22LR, while not an optimal choice for primary self-defense, is nonetheless a very capable defensive cartridge. It's small size and light recoil makes it perfect for a backup role, or for concealed carry in climates or situations that would discourage concealing a larger firearm.
Stock Photo (From let to right) .22 Short, .22 Long, and .22 Long Rifle