=l''IIe/"at L/IrG I CD40-independent areproducedinCD40L-'-miceinresponsetoTD dismutase 1 (Ct~Zn SOO-l). This enzyme cata-

antigens, Howe-: '~ ~ *his paper considerable lyses the dismutation of superoxide to O~ and antibody-isotype switching Protective antibodies in murine Lyme disease arise independently of 0040 Iigand

Fikrig, E. eta/. (1996)

J, ImmunoL 157,1-3

One of the features of an i~mune response to T.dependent ffD) antigens (most proteins) is that B cells usually switch the tsotype of antibody that they produce: the antigen specificity of the anti. body remains the same but its heavy chains change. As e result, the antibody ~¢omes more effective (for example to remove pathogens) because Its capacity to mediate effects such as phagocytosls or complement.mediated lysis Increas~,

tsotyoe switching (from lgM to IgG, IgA or IgE) ~urlng a TO Immune response ts dependant o=~ T.cell=B.celt contact, and w~s tt~ought to toe de+ pendent on the Interaction of the receptor CD40 on B cells with Its 39 kDe Ilgand (CD40L) on actI. voted T eell~', mI~ that lack either of these two molecules do not produce an Isotype-swltched response to TD antigens, and humans with a natural defect tn CD40L, rendering it incapable of btn~ng CD40 (X.llnked hyper IgM syndrome), also have defects in Isotype switching in response to TD antigens,

In this pal~r, the consensus that isotype switching to IgG is CD40 deper~lont is challenged. This group studied the immune responses to the agent that causes Lyme disease, 8orrelia burgdofferL CD40L "~ (knockout) mice and nor- mal controls were infected with B. burgo~rferL Oespite the fact that resolution of arthritis in the in~ l~ l mice is thought to be antibody mediated,

seventy and rQsolution in the two groups of mice were similar, Protection against infection, and prob-

~olution of the a ~ , were likely to be anti- m~liated rather than cell mediated b~'.~use

serum from ~nf~¢10d C040L "~" mice transferred to immunedeficient mice protected the recipients.

Other studies have shown that none of the four s u b c l a ~ of IgG (IgG1, IgG2a, IgG2b and IgG3)

4O8

quantities of bacterium-reactive IgG2b were in- duced in infected CD40L -~- mice. Further analysis by western blotting showed that the IgG2b in the serum of these mice reacted to only a subset of the proteins compared with IgG2b from control mice, indicating that responses to some proteins remained CD40L dependent.

This report suggests that there are alternative CD40L-independent pathways that can lead to isotype switching in response to protein antigens, and that they could depend on the antigen's struc- ture, This reflects a common theme in immunology - there can be more than one means of acheiving the same end,

Andrew Heath Lecturer, Department of Medical Microbiology end Sheffield institute for Vaccine Studies, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK $10 2RX,

Free radical production implicated in ALS A gain of function of an amyotrophic lateral =clerosiHssociated Cu, Zn,~upetoxide dismutue mutant: an enhancement of free radical formation due to an Increase in K m for hydrogen peroxide

'Vim, M.B. eta/. (1996)

Proc. Natl. Acad, SoL U. S. A. 93, 5709-5714

Human motor neuron diseases, including amyo- trophic lateral sclerosis (ALS), are degenerative disorders of motor neurons of the cortex, brain. stem and spinal cord, ALS has a worldwide preva- lence of around 5t100 000 and is inherited as an autosomal-dominant disorder in 10% of cases. About 20% of these inherited cases are of early onset and are associated with mutations in the gene encoding copper-zinc superoxide

H202 (202- + 2H+ --.> 02 + H202). It was thought that mutations in SOD-1 wo,JId

lead to a reduced SOD activity in cells, leaving them vulnerable to oxidative damage from super- oxide. However, in transgenic mice expressing the Gly93Ala mutation of $OD-1 - wl]ich show loss of motor neurons, wallerian degeneration of the ventral roots and denervation atrophy leading to limb weakness and death - the SOD-1 activities were 2-3-fold higher than normal, and the spc.;ific activity of the mutant enzyme was higher than the wild type. Similarly, the enzyme extracted from patients with SOD-1 mutations has not shown consistent reductions in dismutase activity. It has therefore been concluded that the mutant enzymes must act through a dominant gain of cytotoxic function.

This paper reports a possible mechanism tel that gain of cytotoxtc function. The authors have previously shown thai an additional function of Cu/Zn SOD-1 is to. generate free radicals such as the hydroxy~ radical during a peroxidation reaction that uses lie own dtSmutalion product (H~O~) as substrata, and the production of scavenger, derived radicals, using anionic radicaB scavengers and Hag ~ as substrates, The free radicals escapQ from the active si:e el the enzyme into the bulk solution. Using purified Cu/Zn SOD-1 overex. pressed in insect sB ceils, the authors demon- strate here that the Gly39Ala mutant enzyme has a similar (93%) superoxlde dismutase activity to that of purified wild-type enzyme, The P/,, reduc- tion in activity is consistent with the ~ reduction in Cu ~" content in the mutant enzyme. However, the free-radical-generating activity of the mutant enzyme was consistently enhanced compared with the wild type, owing to a lower K~ value for H20 z The authors argue that the enhancement of free-radical-generating function by the mutant SOD-1 could be the gain of cytotoxic function that has been postulated. In that case, the death of motor neurons in ALS could result from an el- evation of hydroxyl radicals, which could react directly with biomolocules (such as proteins), or through the production of free radicals from anionic radical scavengers (such as the neurotransmitter glutamate). This could be consistent with the dis- ruption of glutamate levels in ALS motor neurons.

Copyright 01996 Elsevier Science Ltd, All fights reserved. 1357 - 4310/961515.00