IMMUNODEFICIENCY AND IMMUNOBIOLOGY

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VOLUME 47 MAY 1971 NUMBER 5

COMMENTARIES

IMMUNODEFICIENCY

AND

IMMUNOBIOLOGY

LMOST 20 years ago in this journal,

Bru-ton’ described a young boy afflicted

with recurrent severe infections, who

lacked gamma globulin. His description

identified a new disease and heralded a

new era in immunobiology.

“Agammaglo-bulinemia,” the term he coined, described a

condition of immunodeficiency in a manner

analogous to the use of the term “anemia” in the description of abnormalities in

eryth-rocytes. The delineation and treatment of

immunologic defects require a conceptual

framework for the understanding of

im-mune responses in man, just as the specific

diagnosis and therapy of anemia require

knowledge of iron metabolism, hemoglobin

synthesis, and erythrocyte production. In

the absence of a logical basis, the multitude

of syndromes are no more than a

kaleido-scopic, unintelligible jumble of eponyms.

In this issue is printed a report,2 from a

meeting arranged by the World Health

Or-ganization, which provides just such a

framework.

It

is an annotated itinerary

through difficult but fascinating territory.

The authors review current knowledge of

the immune response and detail existing

methods to assess the immune state. They

provide a careful, rational definition and

classification of immunodeficiency states

based on this knowledge.

Recommenda-tions for appropriate therapy follow.

Con-siderable order is achieved. In addition, to

achieve even greater order in the future,

the establishment of two international

reg-istries for data on patients with

immuno-deficiencies is announced, and recommen-dations for standardization of diagnostic procedures are given. The report is replete with information.

The classification presented is derived

primarily from current knowledge of the distinction between cellular and humoral

immunity. The differences between

cell-mediated delayed hypersensitivity and

hu-moral antibody responses have been

recog-nized for many years. Recent research

suggests that the distinction results from

dif-ferentiation of stem cells in the bone marrow

into two divergent lymphocyte populations,

both immunologically reactive, each with

separable and identifiable characteristics.

One cell population linked with cellular im-munity, designated T-lvmphocyte (“thymus-de-pendent”), appears to be the longer lived, larger component of the circulating small lymphocyte

pool. In addition to classic “delayed hypersensi-tivity,” “1” cells are thought to be associated with immunologic memory and a host of cell-mediated

immune responses, including a role as “killer” cells in graft rejection, immunosurveillance for malignancy, as well as the release of cytotoxic,

chemotactic, and macrophage activation and migra-tion inhibition factors.

The other cell population, termed B-lymphocyte from dependence in chickens on the bursa of Fabricius (“gut-associated”), is linked with humoral antibody production. “B” cells, probably mainly restricted to lymph nodes, are considered to be the cells that differentiate, proliferate, and become the plasma cells that produce immuno-globulin antibodies.

T cells may interact at times with B cells; T

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cells can release factors that induce mitosis in other lymphocytes. With some antigens they may stimu-late antibody production in B cells. Thus, while T cells may not produce immunoglobulin antibody themselves, they may act both as part of the im-munologic memory, and as the amplification sys-tem for antibody synthesis by B cells.

The classification of primary

immunodefi-ciency disorders proposed in the report is based on this concept of the cellular basis

for the immune response; that stem cells

differentiate into two populations, T cells associated with cell-mediated immunity, and B cells associated with immunoglobulin

anti-body production. On the basis of this

hy-pothesis, if stem cells are absent, or if

dif-ferentiation and multiplication fail to occur,

a combined immunodeficiency state should

result, exhibiting defects in both cell-medi-ated and immunoglobulin antibody re-sponses. If only B cells fail to differentiate or proliferate, the defect would be solely in immunoglobulin antibody production. Failure of T cell differentiation or

prolifera-tion

would

primarily

affect cell-mediated immunity, but might also limit antibody production to some extent because of inter-action at this level of the two cell types.

The construct to this point is reasonably plain. Many of the immunodeficiency syn-dromes conform well to the model. Some of the syndromes, however, unfortunately cannot he explained or understood on this basis alone. Nothing seems to be totally simple in biology-or in many other worth-while endeavors. To the degree that man’s

survival as a species depends upon diversity

rather than uniformity, simple answers

have a tendency to be wrong. This becomes

strikingly manifest when the varied

syn-dromes involving immunoglobulins in the

immunodeficiency states are considered.

If antibodies were a single protein spe-cies, a halcyon transient fantasy, it would be

conceptually plausible to postulate a single

structural gene defect for

agammaglohu-linemia. Several human disease models ex-emplifying this type of genetic defect are

known. However, there are several types of

immunoglobulin and, as the report states,

“the problem is much more complicated.”

Although all immunoglobulins appear to be made up of four-chain units, and although there is much congruence among the sub-units of the different immunoglobulin classes, there are apparently a large number of genetic loci involved. The report details these points, and indicates that to date no isolated immunoglobulin deficiencies have been found which can be ascribed to single structural gene defects. Similar difficulties exist for an explanation of partial deficien-cies of specific immunoglobulins on the ba-sis of regulatory gene defects. At this time, even though some of the immunodeficiency states clearly appear to be genetic (infan-tile X-linked agammaglobulinemia, for ex-ample), no simple mechanism related to

specific genetic control for structure or rate of synthesis of immunoglobulins per Se, has been found in primary immunodeficiency

disorders.

At this point, existing understanding of the immune response begins to falter. The construct fails to provide a framework on which we can hang, in a logical fashion, the varied findings of the many immuno-globulin aberration patterns found in the so-called “dysgammaglobulinemias.” For ex-ample: the many patients with immunodefi-ciency who synthesize 1gM antibody (with an apparent memory system),

but

fail

to synthesize IgG antibody; or the fact that some normal people and many patients

with ataxia telangiectasia fail to synthesize

IgA;

or the phenomenon of “acquired”

im-munodeficiency in patients who were

ap-parently normal in early childhood.

Consideration of these groups of

syn-dromes traverses the boundary of

knowl-edge and supportable hypothesis to become

speculation. But speculation can be valid if

it provides a reasonable explanation of

ob-served facts, and may not only illuminate the diseases involved but, with appropriate

experimentation, might also extend our

un-derstanding of the immune response.

The process for differentiation of stem

cells into T cells and B cells should first be

further extended conceptually. The B-cell

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COMMENTARIES 803

of humoral immunoglobulin antibody, must be assumed to differentiate again into the separate cell lines producing the five (or more) distinct classes of

immunoglobulin-1gM, IgG,

IgA, IgD,

and IgE.

It is possible that there is a requisite biologic sequence to this subsequent differentiation-a

step-wise order for immunologic maturation. If

this is the case, then one group of immuno-deficiency states could be postulated to rep-resent developmental arrests in the stages of the further immunologic development of B cells.

There is evidence to support such specu-lation. It has been shown in several in-stances that the initial humoral antibody re-sponse to several antigens is the production of 1gM; the later, or recall response subse-quently results in IgG synthesis.3 A similar transition is found ontogenetically. 1gM an-tibody appears earlier in life than IgG. The differentiation of the B-cell line for complete, mature antibody synthesis may there-fore involve a transition from 1gM produc-ing cells to cells committed to IgG synthe-sis. The 1gM cell line would precede and be a precursor to differentiation for the devel-opment of cells making IgG antibody. If this should be the case, a developmental ar-rest, either intrinsic or extrinsic, which blocked differentiation of the 1gM to IgG cell transition, would result in an immuno-deficiency state with intact 1gM antibody but defective IgG antibody production. Such patients have been described; they may represent this form of developmental arrest.

A cell line that has been stimulated to produce antibody and has begun prolifera-tion does not increase without limit. Feed-back mechanisms must exist to control pro-liferation and antibody synthesis. In the case of 1gM antibody, there are experimen-tal data which suggest that the

develop-ment of IgG antibody “switches off” 1gM production.4 The findings in patients with some immunodeficiency states support this hypothesis. If the B cells in some patients were unable to progress through the postu-lated transition from 1gM to IgG synthesis,

the feedback mechanism would be

inter-rupted

and

abnormal

amounts of 1gM anti-body should result. This appears to be the

case. In patients with immunodeficiency states involving 1gM and IgG production,

those who make no IgG antibody often have significantly greater 1gM antibody re-sponses than those who, while still immuno-logically deficient, make small amounts of IgG and have lower 1gM levels. Similarly, patients with immunodeficiency with hyper 1gM, when given IgG therapeutically, may demonstrate a decrease in 1gM concentra-tion.6 A block in the feedback control mech-anism could also be reflected in an inade-quate control of the proliferative response. Some patients with nodular lymphoid by-perplasia may represent another example of the interruption of such a feedback control mechanism; the disappearance of the

lym-phoid masses during IgG therapy could be

explained on this basis.

The development of a complete, mature immune response involves not only protein synthesis and regulation; it also must be as-sumed to involve cell localization and orga-nization. Stem cells are believed to reside primarily in the bone marrow. B cells, de-rived presumably from stem cells, are found primarily in lymph nodes, arranged in the germinal centers and follicles. A more strik-ing example is the localization of IgA pro-ducing cells which are found

predomi-nantly in the gastrointestinal mucosa (in

addition to the respiratory and urinary tracts).

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col-onized with 1gM rather than IgA producing cell lines, or is unable to support IgA cells allowing replacement by cells producing 1gM. Among other explanations, it is plausi-ble to postulate a developmental arrest in cell localization-due possibly to an intrin-sic defect of the B-cell line, or to a defect in the gut itself, or both.

Immunocompetence also demands the persistence and multiplication of immune cell lines. In tissue culture it can be shown that the ability of a cell to replicate itself accurately is finite and can be exhausted. Im-munocompetent cells should not be exempt from this process of aging. They are con-stantly stimulated to replicate; indeed their proper function presumably depends on this potential. The concept of immuno-senescence has been proposed-the immune system may “wear out” faster than the other

cell

lines in the body.’#{176}At least two mecha-nisms for accelerated immunosenescence are possible. The first is that the original

cell

line has an inherently diminished po-tential for accurate replication; an “immu-nologic progeria.” A second possibility is

that

a normal

potential for replication is prematurely exhausted by excessive stimu-lation, or by noxious exogenous agents. There is experimental evidence to support the

latter

hypothesis.1#{176}Both processes

could

coexist. Unequal early senescence of

differ-ent types of immunocompetent cell lines is

also possible. The group of patients who has been described with so-called “ac-quired” immunoglobulin deficiency states, who appear to be immunologically normal in early childhood, may represent examples of a mechanism of this type.

These speculations are based on four rea-sonably acceptable general biologic princi-ples which have importance for all human development-cellular differentiation and maturation arrest, regulatory control mech-anisms and feedback interruption,

organo-genesis

and

disruption

of cell

localization,

replicatory potential and senescense. There

are

many

other

equally,

or perhaps more

attractive

possibilities

including

foreign

antigen “recognition” and

“memory,”

the

“afferent” and “efferent” pathways of the

immune response, and the impact of the en-vironment on the developmental process.

All provide

a basis for understanding the diversity of the immunodeficiency states which have been described.

At the same time, the unknowns and the diversity accentuate the probability that each patient with a demonstrated immuno-deficiency needs to be studied carefully to determine both the nature and the degree of the abnormality. It is not possible in these disease states merely to measure im-munoglobulin levels and to give gamma globulin, or to consider indiscriminate bone marrow or thymic transplants. Inappropri-ate therapy may not only mask proper diag-nosis, it is often unnecessary and can be dangerous. The \V.H.O. report emphasizes these points and gives, in detail, the exist-ing methods available to assess the immune state.

The suggested standardization of diag-nostic procedures in the report is an ex-tremely vital point. The further delineation and classification of the immunodeficiency states would be greatly enhanced by com-parability of patient data. Much of the ex-isting confusion may relate to diversity of diagnostic techniques rather than diversity in the biologic expression of immunologic deficiency. Similarly, the establishment of registries for the collection and recording of data is urgently needed to facilitate the translation of information into formulation of concept, as well as better patient care.

Both

recommendations are welcome.

At this point many readers should un-doubtedly ask why so much time, effort, and space is spent in the consideration of such a rare group of diseases. What, if any, justification is there to excuse this emphasis on a subject which may seem so irrelevant

to the major health problems of children. In this age, intellectual elegance or scientific esthetic is not presumably a sufficient vali-dation.

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COMMENTARIES

805

little immediate practical value, does in fact provide critical information needed for the solution of more important common prob-lems. These immunodeficiency states repre-sent superb examples of the “experiments of nature” described by McQuarrie in

1944.’

The study of these natural experiments, combined with careful laboratory research, has allowed the detailed dissection of the phenomenon of immunity in man. The in-vestigation of these unusual diseases has contributed directly to the rapid advances in the field of immunobiology. The proper evaluation of such a patient not only illumi-nates the nature of the particular disease, but offers and often has provided critical clues to the general problem of the mecha-nism of immunity.

There are few other fields in biomedical science where advance has been as rapid,

and

where

new

knowledge has in fact been

applied

so directly and immediately to the cure and prevention of disease, and the provision of health. Immunobiology now

extends

far beyond

the realm

of

infectious

diseases

to the

problems

of the

control

of

cancer and the success of organ transplan-tation. The problems of infection in pa-tients with immunodeficiency states have

extended

our

understanding

and

ability

to

treat

and

prevent

infectious

diseases

in the

normal

population.

The

fact

that

malig-nancy appears unusually frequently in many patients with immunodeficiency has provided vital clues to our consideration for

the

importance

of immunosurveillance

in

the normal

control

of cancer

and

the

treat-ment of neoplasia. The successful clinical studies for replacement of defective cell lines in the immunodeficient have identified crucial factors to be considered in trans-plantation generally. One doubts that Bru-ton,

20 years

ago,

conceived

the

ramifica-tions of his singular case report, or that those immunologists who were intrigued by the unusual findings could have predicted that their interest would lead so far, and so fast.

J

cans is quoted as saying that “science advances in two

ways;

by the discovery

of

new facts,

and by the

discovery

of

mecha-nisms or systems which account for the

facts already known.”1 The recent, rapid progress in immunobiology provides a beautiful case study for the history of scien-tific discovery-the collection of seemingly unrelated observations, and the sudden for-mulation from disparate, apparently irrele-vant facts of new laws which have general biologic importance. The acts of intellectual discovery in the search for truth are de-scribed by PolanyP2 or Bronowski” as ana-logous to artistic creativity.

Those

who

press

for “target

oriented re-search,” who urge “utilitarianism” or “cost effectiveness” and demand relevance in place of curiosity, might do well to study

this case history. Can truly creative

intellec-tual discovery be successfully and effi-ciently directed? Can we effectively predict the research areas which will “pay off,” and

those which should be postponed on

grounds of insufficient relevance? Can one dismiss the importance of the accidental uncovering of the seemingly unimportant, previously unknown?

The

rapid

progress

in immunobiology, and the contribution made to this progress by the study of the rare and complex immunodeficiency states, suggests that direction of research by prediction of future applicability and dismissal of the ap-parently irrelevant may not in truth be the best way to solve important health or man problems.

The

report

of

the W.H.O. Committee on Primary Immune Deficiencies contained in

this issue, although it is directed specifically to a set of unusual conditions, may have rel-evance far beyond these uncommon dis-eases alone.

RALPH

J.

WlmcwooD, M.D.

Department of Pediatrics University of Washington School of Medicine Seattle, Washington 98105

REFERENCES

1. Bruton, 0. C.: Agammaglobulinemia.

Pmi-ATIUCS, 9:722, 1952.

2. Report of the W.H.O. Committee on Primary

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3. Uhr, J. W., and Finkeistein, M. S.: Anti-body formation. J. Exp. Med., 117:457,

196.3.

4. Uhr, J. W., and Moller, C.: Regulatory effect

of antibody on the immune response.

Ad-vanc. Immun., 8:81, 1968.

5. Ochs, H., Davis, S. D., and Wedgwood, R. J.:

Immunologic responses to bacteriophage OX 174 in immunodeficiency diseases. In prep-aration.

6. Stiehm, E. R., and Fudenberg, H. H.: Clinical

and immunologic features of

dysgamma-globulinemia, type I. Amer. J. Med., 40:805, 1966.

7. Unpublished observations.

8. Eidelman, S., Davis, S. D., Lagunoff, D., and Rubin, C. E.: The relationship between

intestinal plasma cells and serum IgA in

man. (Abst.) J. Clin. Invest., 45:1003, 1966. 9. Eidelinan, S., and Davis, S. D.:

Immuno-globulin content of intestinal mucosal plasma-cells in ataxia telangiectasia. Lancet

1:884, 1968.

10. Keast, D.: Immunosurveillance and cancer.

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11. McQuarrie, I.: Experiments of nature and

other essays. Lawrence, Kansas: University

of Kansas Press, 1944.

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Chi-cago: Phoenix Books. The University of

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New York: Harper Torchbooks. Harper and

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1971;47;801

Pediatrics

Ralph J. Wedgwood

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