There really is a huge difference between and .22+ and a Mark III. Still more between the .22 and the IV. They are all really great sounding amps IMHO but quite different.
Here are the Major differences:
Sound -
.22+: EL84 based. These tubes tend to break up fairly early and provide a nice power tube distortion at reasonable volumes. Produces a more "British" tone character. Very mid-range heavy and somewhat compressed. Good clean sound but limited headroom. Very aggressive lead tone with tightly focused mid-range crunch. Cleans become more gritty as the volume goes up.
Mark Series Amps: 6L6 Based. Much less power amp distortion even at high volumes (although this can be manipulated see below). Warmer overall tone with more low and high-end emphasis. Has wonderful cleans with tons of headroom. Marks are renowned for their ability to produce incredible sustain, harmonics and note definition in both Clean and High-gain settings. Marks can also produce insane levels of pre-amp distortion paired with a massive power section to push it out.
The Mark's power options also add the ability to alter the output tone. However there are many optional variations on the III (60, 100/60, Simul, Coli...) while most modes (and a few more) are built into the IV. Probably the most interesting is Simul-class which blends Class A sound with Class AB power. This mode also allows you to mix EL-34 & 6L6 tubes to change the overall tone color. THe Mark IV has a very flexible power section, that can be set up with small switches on the back, giving you a variety of tone and wattage options.
Functionality -
The Mark III & IV win this battle easily. These are both 3 channel amps that provide much more flexibility to jump from Fenderish clean, to chunky/crunchy rhythm, to Searing lead. The IV has the added advantage of further separating the tone stack and output volumes for each channel and adds a much needed footcontroller to manage it all. The III has more shared tone and volume controls. The V (finally) completely separates the pre-amps for each of the 3 channels like Mesa has done with nearly every other amp they have made in the past 10-15 years.
The .22 has a shared tone stack and provides a gain-boost function rather than an actual 2nd channel. This was fixed in the Studio Caliber / DC-2 redesign where a second independent channel was added for lead.
I'm sure there is more I'm leaving out but that's a decent overview.
