Document DMe5J62oDnO8NQ6QM1R0gkwbQ

7^ x ^ ? 2- > Cellular umiuuity Jam es F. Jones, Richard B. Johnston, Max D. Cooper Cellular immunity is mediated by spe ficity but that macrophages were required cifically activated lymphocytes and serves to effect the response. In addition, if the to enhance nonspecific immune functions. thymus of the animal was removed, nor Unlike immunoglobulins which generally mal development of cellular immunity enhance protection against circulating or was impossible. cell-free microorganisms or toxins, the This chapter will explore the develop cellular immune response has evolved to ment and maturation of cellular immu rid the host of infected or otherwise al nity and its constituents, the thymus, lym tered host cells. Cell mediated immunity phocytes and their products, and (CMI) is responsible, therefore, for reso macrophages; in addition, the major con lution or prevention of infection caused genital and acquired CMI deficiency by intracellular bacteria (Listeria mono states will be summarized. cytogenes), certain viruses, fungi, and pro tozoa, and mycobacteria. CMI is also re sponsible for rejection of foreign tissue BIOLOGY OF CELLULAR IMMUNITY grafts and for elimination of some cancer The thymus is responsible for convert cells. ing hematopoetic stem cells into immuno These responses have been previously competent lymphocytes, which it supplies termed "delayed hypersensitivity." This to the rest of the body. The thymus is phenomenon, however, is just one mani formed along with the parathyroid glands festation of CMI. although the first to be from specialized epithelial cells lining the* recorded. In the early 1800s. Jenner ob third and fourth pharyngeal pouches. As served erythema and induration in the the thymus migrates in early embryonic skin of individuals approximately 24 life to its final location in the anterior part hours after innoculation of his cow pox of the mediastinum, stem cells begin to vaccine in those who had had small pox enter it. The epithelial thymus appears to or who had been previously vaccinated. secrete hormones at this stage which initi Koch then studied the reaction in great ate this migration. Once under the influ detail in the host response to infection ence of the thymic environment, these with tuberculosis. But it was not until the cells differentiate into small lymphocytes early 20th century that Landsteiner and and multiply rapidly as they migrate from Chase determined that delayed hyper cortex to medulla. From the medulla, sensitivity was due to specific cells. Other thymic lymphocytes (T lymphocytes) en-- workers subsequently determined that ter the bloodstream bound for peripheral lymphoid cells previously exposed to the lymphoid tissues. The thymus gland elab antigen in question arc required for spcci- orates other humoral substances which 5 l:1 Cclluliir Inmumilv 75 enhance the functional capability of its sor T cells, antibody-dependent cytotoxicity daughter lymphocytes in exirathymic lo T cells, and natural killer cells, as well as cations. T lymphocytes exit the circulat two types of primary effector cells. Helper ing bloodstream and collect in the deep T cells enable B lymphocytes to differen cortical areas of lymph nodes and cuffs tiate into antibody-secreting plasma cells. around the small straight arteries of the This effect is particularly important when spleen. After transient residence in these the B cell has been stimulated by certain thymic-dependent areas of the peripheral antigens, typically proteins, referred to'as lymphoid tissues. T lymphocytes enter the T cell dependent antigens. T cell help is lymphatics and via the lymphatocovenous more necessary for production of IgA, communications, reenter the bloodstream. IgE. and IgG antibodies than for produc This circular traffic pattern does not in tion of IgM antibodies. T helper cells also clude a revisit to the thymus. Recognition enhance T cell maturation when .stimu of foreign substances by both B and T lated by specific or nonspecific triggers. lymphocytes is apparently accomplished Suppressor T cells act as regulators of B by surface receptor units. It is thought cell maturation, inhibiting the process that each lymphocyte carries surface re and thereby controlling production of ceptors capable of combining with a antibody. Suppressor T cells are thought single antigen or a small group of closely to play a role in other immune regulatory related antigens. Receptors on B lympho phenomena including immunologic toler cytes are clearly established as immuno ance and antigen competition. Antigens globulin molecules. Specific antigen re presented to T cells in limited amounts ceptors on -T lymphocytes may also be appear to lead to T helper activation immunoglobulins or immunoglobulin whereas excessive amounts of antigen in like molecules. On contact with the ap duce T suppressor activity. propriate antigen. B lymphocytes divide Lymphocytes which lack typical T or B and differentiate into plasma cells and T receptors (Null cellr' but which have Fc lymphocytes are stimulated to begin a receptors recognize ; tibodies on infected complex series of events, including secre cells and lyse them. This mechanism is tion of several biologically active factors known as antibody-dependent cell-medi and transformation into blast cells. Lym ated cytotoxicity (ADCC). A fourth type phoblast transformation is followed by di of T lymphocyte is the natural killer cell. vision into two daughter T lymphocytes These cells require no specific antigenic bearing surface receptors for the same an stimulation, but are able to lyse infected tigen as that to which the parent is re or cancerous cells (I). Their activity is en sponsive. In this way, "immunologic hanced by interferons. Two other types of memory" is established in the form of an effector T lymphocytes are produced expanded population of lymphocytes ca upon specific stimulation; T killer cells pable of recognizing and initiating the im are capable of lysing infected or "foreign" mune response to the antigen. Lymphob cells (no antibody required). The second last transformation and products of effector cell produces lymphokines, a con lymphocyte factors by T lymphocytes glomerate of biologically active factors may also be stimulated nonspecifically by with a variety of functions. plant mitogens such as phytohemaggluti nin (PHA). LYMPHOKINES SUBPOPULATIONS OF T LYMPHOCYTES Studies of cell surface membrane re ceptors and of cell functions indicate there are at least six functional subpopulations of T lymphocytes. These have been labeled helper T cells, suppres On stimulation with specific antigens or appropriate mitogens, both T and B lym phocytes produce lymphokines. At least a dozen such substances have been de scribed. primarily in terms of the activity they promote rather than their physicalchemical properties. It seems likely, there fore. that some of the different activities 76 INFECTIONS IX CIULDUMX may be mediated by the same substance. system. Lymphokines arc then products Nevertheless, the elucidation and partial which amplify the host response to a purification of several of these lympho given antigen or insult with a purpose of kines have provided at least a tentative mounting a concentrated effort to main explanation of how T lymphocytes com tain homeostasis. municate with macrophages. and other lymphocytes to achieve the eventual re jection of invading microorganisms, for ROLE OF THE MACROPHAGE eign tissue, or cancer cells. The peripheral blood monocyte is One of the best defined lymphokines is transponed from its binhplace in the migration inhibitory factor (MIF),`. so marrow to its eventual home in the retic named because it inhibits migration of uloendothelial system where it becomes a macrophages from capillary tubes. The free or fixed mononuclear phagocyte or assay is performed in the following man macrophage; this process may include a ner: A suspension of macrophages, sensi sojourn in the thymus (3). Two divergent tized lymphocytes from immunized do roles have been proposed for macro nors in a sensitizing antigen are placed in phages; whether the same cells participate capillary tubes; the cells are packed by in each is unclear. The first and more centrifugation; and the extent of migra primitive role is that of a phagocytic killer tion out of the open lube is measured. cell. The second role is regulation of the Lymphocytes and antigen can be re immune response; in many instances the moved to show that migration of a puri two roles arc interrelated. fied macrophage preparation can be in In a nonimmune host, macrophages hibited by the cell-free supernatant of a initially come in contact with new anti mixture of sensitized lymphocytes and an gens in regional lymphoid tissue. Foreign tigen or by a thermosiabile acidic glyco material is engulfed and may either be de protein purified from this supernatant. stroyed or persist in the cytoplasm. Anti This protein may be responsible for the gens are somehow "processed" and re activation of the macrophages as well. main on the surface of the macrophage. Chemotaciic factors for both macro These cells then "present" the antigen to phages and neutrophils have been dem T or B lymphocytes to initiate lymphocyte onstrated in lymphocyte-antigen super activation and effector processes de natants using Boyden chemotaxis scribed above. During certain infections, chambers. These factors are distinct from these cells come under the influence of an each other and from MIF. Cytotoxic or intense stimulus and. develop morpho lymphotoxic factors have been described logic and functional alterations indicative which are able to cause the death and of a stale of activation. The morphologic lysis of target cells in culture. Mitogenic changes consist of increased cell size and or blastognie factors can be prepared by increased numbers of mitochondria, lyso stimulating the sensitized lymphocytes somal granules, and fluid-filled vesicles from an immunized donor with specific with the cell. In terms of function, acti antigen; the supernatants call sensitized vated macrophages exhibit increased lymphocytes to transform into lympho pinocytosis, enhancing spreading on glass, blasts and divide. Soluble factors that can and. most importantly, increasing the kill enhance or suppress antibody production ing of microorganisms. have been described. Interferon elabo The principal infections resulting in rated from virus-infected or antigen-stim macrophage activation are due to organ ulated lymphocytes can inhibit virus rep isms which are pathogenic because they lication in other cells. Leukocyte can survive inside phagocytic cells, viz. vi inhibitory factor acts to inhibit the migra ruses. fungi, parasites, and bacteria such tion of polymorphonuclear leukocytes. as Brucella, Listeria, and Mycobacterium.- These and the other substances summa It is clear from the work of Mackaness rized by Rocklin (2) elicit responses from and others that the small lymphocyte is or clTcct other components of the immune integrally involved in the process of i J It [p] 5 if Cellular Immunity 77 macrophage activation (4). It has been sult. lymphokines would be elaborated shown, for example, that the transfer of which would expand the cellular immune small lymphocytes from an animal im response. Lymphocytotoxin might di mune to the tubercle bacillus enables the rectly injure the invader. Chemotactic recipient to,rapidly accumulate activated factor might recruit macrophages which macrophages at sites of tuberculous infec could become activated and more micro tion. as if the recipient himself were im bicidal on exposure to MIF. If the invader mune. Moreover, the slate of enhanced were a virus, interferon would block its immunity which has been transferred is replication in infected cells. These events specific for the immunizing antigen: it can would be amplified in lime by the replica be elicited only by exposing the trans tion of immune T lymphocytes, possibly ferred lymphocytes to that antigen. How enhanced by mitogenic factor and per ever, once the macrophage has been acti haps enhanced by the instruction of other vated. it exhibits a nonspecific increase in T lymphocytes through the action of microbicidal activity which may be di transfer factor, which could convey spe rected against any organism. Thus, an an cific recognition capabilities to neighbor imal which received tubercle bacilli along ing cells. Depending on the balance be with lymphocytes from a donor immune tween the innoculum size and the to tuberculosis becomes resistant to chal virulence of the infecting organisms and lenge with Listeria because of the acti the rate and intensity of the host response, vated macrophages which are developed. the infection would be eliminated or In other words, sensitized lymphocytes would spread systemically. generated by prior exposure to an antigen Macrophages may also control T lym can. on exposure to that antigen, excite phocyte responses. At least in certain in previously resting macrophages to a state vitro situations. lymphocyte response to of activation during which they have en mitogen and antigen are suppressed when hanced microbicidal activity for any or macrophages comprise greater than 5CFe ganism. ` of the mixture. Whether this phenomenon The mechanism by which macrophages occurs in vivo, has not been elucidated. become activated has not been elucidated. However, it has been shown that purified MIF can induce in cultured-macrophages CELL-CELL COOPERATION some of the morphologic, metabolic, and T and B lymphocytes interact directly functional alterations that comprise the with one another, with macrophages, and activated state, including an increased ca with antigens during the response to for pacity for ingestion and killing of bac eign substances or altered self substances. teria. Thus, it seems likely that it is Inherent in these reactions are two basic through MIF that sensitized lymphocytes principles: I) recognition of antigens that induce macrophage activation. are different from self, and 2) communi By synthesizing what is known of cation among autologous cells, ic, B-T macrophage activation with what is cell interactions. In humans, each of these known about the activity of lymphocytic phenomena are dependent on the HLA factors in vitro, it is possible to construct a (Human Leukocyte Antigen) system, a se hypothetic model of the events which sur ries of antigens which are expressed on round the body's resistance to infection chromosome 6 and appear to be associ by intracellular microorganisms in the ated with immune responses. immune host. Since these organisms have HLA antigens are present on all cells the ability to survive inside phagocytes, (except erythrocytes). This label was first phagocytosis by polymorphonuclear leu studied in relation to the development of kocytes would not halt the infection, even cancer in animals, but soon was recog in the presence of adequate antibody lev nized to be of prime importance in trans els. Within 12 hours. T lymphocytes plantation rejection. would be attracted to the area and would The immune response to infection was encounter the invading organism. As a re subsequently found to be under the same 7,S' INH-XTIOXS IX CIllLDKl'X genetic control as the HLA system. In a patient may die of generalized vaccinia fact, it has been hypothesized that this following smallpox vaccination, of dis system of identification of host cells seminated herpes simplex infection, or of evolved as defense against virus infections fulminant chickenpox or measles. Con became important (5). Viruses replicate in versely. no belter evidence of normal T animal cells by using the host's genetic lymphocyte function can be obtained material and production apparatus. Thus, than the history of a normal response to virus antigens frequently become fused chickenpox, herpes zoster, measles, or with host antigen. A system of discrimina live-measles virus vaccine. (It should be tion to recognize virus-infected cells-vs emphasized at this point that live virus noninfecicd cells appeared to be neces vaccines should never be administered to sary so that host defense mechanisms an infant with possible immune defi could intervene in a selective manner. ciency.) Since contact hypersensitivity is a The HLA system fulfills the criteria of manifestation of cellular immunity, his identifying normal host cells, so that cells tory of poison ivy or other contact allergy with additional antigen or altered host- also indicates normal T lymphocyte func antigen (infected cells) may be removed. tion at the time of the event. Experiments in both human and ani Further investigation of patients whose mal subjects have shown the Tk function history suggests defective cellular immu (cell-mediated cytotoxicity) is dependent nity should begin with determination of on HLA (A. B) identity between lym the absolute lymphocyte count, x-ray of phoid cells and infected cells. Thus, lym the chest for the thymic shadow, and ap phocytes must recognize both normal and plication of skin tests for delayed hyper altered antigens on infected cells (6). sensitivity. as summarized in Table 1. An Another type of genetic restriction tigens used for skin testing should be found in the HLA region of chromosome stored in the lyophilized state at 4 C and 6 is based on another antigen called la. Ia reconstituted shortly before use. care may control cell-cell interaction per se. being taken that the expiration date has but not' cytotoxicity reactions. In other not been reached. The injection of 0.1 ml words, communication between T and B should be made intradcrmallv with a 25- cells. T cells and macrophages, and T-T or 27-gauge needle. Reactions should be cell interactions may be specifically re examined si 4 to 6 hours for the appear lated to la. rather than HLA-A or B. This ance of an antibody-mediated Arthus re requirement appears to be independent of action. which could be confused with a the presence of antigens. delayed hypersensitivity response. Most infants who have received two DPT (dip- iheria, pertussis, tetanus) immunizations CLINICAL EVALUATION should have a positive delayed reaction to tetanus toxoid (7), and most children over It is clear from the study of patients 12 months of age should have a positive and animals with defective cellular immu delayed response to Candida antigen and nity and from correlated laboratory re streptokinase-streptodomase (SK.SD). search that cellular immune mechanisms Tetanus toxoid should be used at a 1:100 are required for defense against infection dilution; if the response is less than a 5- by intracellular parasites, including fungi, mm induration, a 1:10 dilution should be viruses, and some bacteria. Therefore, administered. Candida and Trichophyton even in the presence of adequate amounts antigens should be diluted 1:100 before of antibody, deficient T lymphocyte func use in adults and 1:10 for children but tion leaves the host susceptible to per should be given undiluted if the initial sistent or life-threatening disease due to testing is negative. Streptokinasc-strepto- microorganisms which arc mildly patho dornasc should be given at a concentra genic or even commensal in the normal tion of 5 units of streptokinase per 0.1 ml: host. For example, candidiasis may be se if no reaction occurs. 40 units should be vere and chronic in spite of all therapy, or given. A positive response to any of.the o !M Cellular Immunily 79 TABLE I. Clinical Assessment ol Cellular Immunity Method Material Normal Finding History Lymphocyte counts Chest x*ray Skin tests Peripheral blood Candida (HotiisterSiier) STKrtScDho(pVtahnydioanse()H(ollelidseterrle-S) tier) PPD. histoplasmin, coccidoidin Tetanus toxoid (Lilly) Poison ivy. contact hypersensitivity No difficulty with thrush, viral inlec tions. or vaccines >4.000/cu mm in first yea: >2.000/cu mm in childhood Visible thymus >5-mm induration alter 48 hr >5-mm induration alter 48 hr >5-mm induration alter 48 hr >5-mm induration after 48 hr >5-mm induration alter 48 hr SKSD . streptokinase-streptodornase: PPD. purified protein derivative. skin lest antigens suggests strongly that tion and divide, radiolabeled nucleic acid cellular immunity is intact. (eg. tritiated thymidine) is incorporated T lymphocytes can be identified and into new' cells as DNA. The culture is ter enumerated in samples of blood or lym minated by precipitating the cellular ma phoid tissues. One convenient technique terial with acid, and the precipitated ra .for distinguishing T lymphocytes from B dioactivity count reflects the amount of lymphocytes is- by virtue of the chance nuclear material formed. Lymphocytes discovery that T lymphocytes can bind from patients with defective cellular im sheep erythrocytes (S). In this assay, the munity respond subnormally to the mito lymphocyte mixture is incubated at a genic effect of PHA. A variety of other 1:100 ratio with sheep erythrocytes at stimuli can be used to activate lympho room temperature for 30 minutes and cytes in culture, including specific anti then overnight in the refrigerator. The gens and cells of a second individual, ie, cells arc then resuspended by gentle mix in the mixed lymphocyte culture. ing and examined by counting the per MIF and other lymphokine activity, as centage of lymphocytes which bind sheep well as T cell subset function, may be de erythrocytes in a rosette pattern. This pro termined by the assays mentioned above cedure is referred to as the E-rosette or T- in which patients' lymphocytes are tested roseue assay. T cells can also be directly in the presence of antigen to which the enumerated by their reaction with anti lymphocytes have been exposed. serum to the antigens found on T lym phocytes but not on B lymphocytes. SYNDROMES OF DEFICIENT T cells can also be identified by specific CELLULAR IMMUNITY membrane antibodies or by rosetting with In respect to pathogenesis, it is artificial IgM or IgG coated erythrocytes yielding to separate all defects of cellular immu Tfi (helper) or Ty (suppressor) subjects re nity into one category distinct from de spectively (9). fects of immunoglobulin synthesis. How If the delayed hypersensitivity skin tests ever, an absence or even a partial are negative, other tests of cellular im depression of cellular immunity bears mune function must be employed, since common and severe clinical consequences skin tests may be negative in a small per which dominate the symptomatology and centage of otherwise normal individuals, the problems of management. Moreover, especially if they have a concurrent viral these syndromes illustrate most of the illness. Measurement of the response of basic concepts described above. There peripheral blood lymphocytes to PHA is a fore. for the purposes of this discussion, valuable screening test for T lymphocyte all syndromes of deficient cellular immu abnormalities. When the PHA induces nity have been grouped and subdivided, lymphocytes to undergo blast transforma as summarized in Table 2. according to is,w i.n t i x t i o x s c i i i u j k i -x TABLE 2. Defects of Cellular Immunity Diagnostic Studies Abnormality Suggestive Confirmatory Without immunoglobulin deficiency Chronic mucocutaneous candidiasis Thymic hypoplasia Thymic dysplasia with abnormal immuno globulin synthesis Secondary deficiencies Combined with immuno globulin deficiency Severe combined immuno deficiency Immunodeficiency with dwarfism Ataxia-telangiectasia Wiskott-Aldrich syndrome Immunodeficiency due to enteropathy Immunologic amnesia Thymoma Candida skin test Thymic shadow: skin tests: im munoglobulins (normal): calcium Thymic shadow: skin tests: im munoglobulins and antibodies: lymphocyte counts Thymic shadow; skin tests: im munoglobulins and antibodies: lymphocyte counts Thymic shadow: skin tests im munoglobulins and antibodies; lymphocyte counts Thymic shadow: skin tests: im munoglobulins and antibodies: lymphoucte counts: bone x-rays Skin tests: immunoglobulins: lymphocyte counts Skin tests: immunoglobulins: lymphocyte counts: isohemag glutinins: platelet count Skin tests: immunoglobulins: lymphocyte count: albumin Skin tests: immunoglobulins: lymphocyte count Skin tests: immunoglobulins: lymphocyte count: chest x-ray Lymphocyte transformation (normal); MIF Lymphocyte transformation: parathormone response: E rosettes Lymphocyte transformation: E rosettes Lymphocyte transformations to nonspecific and specific stimuli LyEmrpohsoeclyletes:traadnesntoorsminaetion; diaminase. nucleoside phosphorylase assays Lymphocyte transformation; E rosettes Lymphocyte transformation Lymphocyte transformation (normal to PHA): antibody response to polysaccharides Gastrointestinal tract studies Lymphocytotoxic antibody; response to antigens Surgery MIF, migration inhibitory factor; PHA. phytohemagglutinin. whether or not there is an associated im these patients have an increased incidence munoglobulin deficiency. of antibodies to mitochondria, parietal cells, or adrenal, ovary, thyroid, or para Without Immunoglobulin Deficiency-- Chronic Mucocutaneous Candidiasis thyroid tissue. Evaluation of cellular immunity has given variable results from patient to pa Patients with this disorder suffer tient: almost all patients have had a nega chronic and severe candidiasis of the buc tive Candida skin test: many have had a cal mucosa, tongue, vagina, nails, and negative response to other delayed hyper skin. Invasion of deeper tissues rarely oc sensitivity skin tests: and lymphocytes curs. Many cndocrinologic abnormalities from most have transformed normally in have been associated with this entity, of vitro on exposure to PHA or specific anti ten appearing years before or after the on gens including Candida albicans. It has set of chronic candidiasis. The more com been shown that some patients' lympho mon ones include hypoparathyroidism. cytes may lack the ability to elaborate Less common arc diabetes, pernicious MIF on exposure to Candida. This defi anemia, and gonadal dysgenesis. This ciency may account for the failure of local relationship has not been explained, but ~ surface immunity in the presence of nor-  Ni Cellular Immunity 81 mal lymphocyte transformation . on ex delayed hypersensitivity skin tests, lym posure to the organism. Treatment of the phocyte transformation by PHA or anti cndocrinopathy, if present, may cure the gens. MTF production, graft rejection, and candidiasis: no other treatment, including resistance to viral, fungal, and bacterial toxic doses of amphotericin B. has given infection. Immunoglobulin levels may be more than temporary relief. However, it normal or even elevated. The quality or has been demonstrated that if lesions quanity of the antibody response in these have been cleared with amphotericin B patients has not been clearly elucidated. therapy, their recurrence may be sup The few who have been studied when not pressed by the administration of transfer deathly ill have had a normal primary re factor obtained from donors with normal sponse to a variety of antigens but have cellular immunity to C albicans; this treat had another primary response rather than ment may prove effective for some pa a secondary response on restimulation tients. with the same antigen. As was predicted from studies of the role of the thymus in experimental animals, implantation of Thymic-Parathyroid Hypoplasia fetal thymus tissue into the abdominal waU has restored T lymphocyte function Faulty embryonic development of the and the ability to resist severe infection in third and fourth pharyngeal pouch epi patients with the syndrome. There is evi thelium can result in congenital absence dence that the thymic implant supplies a of the epithelial thymus and the para humoral factor that enables stem cells to thyroid glands. Infants with this disorder mature into T cells. suffer tetany and recurrent severe infec Several children with this affliction tions. including meningitis, septicemia, (also known as DiGeorge's Syndrome) peritonitis, subcutaneous abscesses, and who were immunodeficient at birth, have pneumonitis due to bacteria, viruses, or spontaneously regained immune function Pneumocystis carinii. Diarrhea, persistent after 3 to 4 months of life. The cardiac de m ucopurulent rhinorrhea. oral can fect may dictate the final outcome in these didiasis, and growth retardation are other patients. common manifestations. Developmental abnormalities of related anlages and their clinical consequences have been a promi nent part of the syndrome and have in cluded. in various combinations, esopha Thymic Dysplasia With Immunoglobulin Synthesis geal atresia, right-sided aortic arch, As originally described by Nezelof, this congenital heart defects, thyroid hypo disorder was believed to represent thymic plasia. and facial anomalies, consisting of dysplasia (irregularly organized epithelial micrognathia, shortened philtrum of the stromal cells with few lymphocytes and upper lip, midline cleft of the nose, high- no Hassall's corpuscles) with complete arched or cleft palate, hypertelorism, and sparing of antibody-producing machin malformed, asymmetric, or low-set ears. ery'- ic, a pure T lymphocyte defect like The glands may be hypoplastic rather that of thymic aplasia but due to an ab than absent, in which case the tetany and normally functioning thymus. As addi recurrent infections are less severe and tional cases have been described, how may disappear in time. ever. it has been shown that these patients Although a tragic birth defect, in its do not synthesize antibodies normally in complete form the syndrome of thymic- spite of their normal immunoglobulin lev parathyroid hypoplasia has represented els. Moreover, other patients with the an opportunity for delineation of the role pathologic picture of thymic dysplasia of the thymus and T lymphocytes in hu have had either deficient IeG and IgA man immunity. Indeed, patients have and normal Ig.M. isolated IgA deficiency, been found to lack all n vitro and in vivo or another partial immunoglobulin de manifestations of T lymphocyte-mediated fect. In one instance, the partial defect immunity, including positive reaction to differed in two siblings. Some of these pa- 82 LNTECriOXS IS CHILDREN tients have lived beyond 2 years of age. logic changes; lymphocyte counts have Their clinical pictures have been very occasionally been nearly normal in this similar no matter what the immunoglobu form. Transplantation of histocompalible lin pattern. Thus, it is not possible to sep bone marrow cells (usually from a sibling) arate these disorders on meaningful clini or liver cells from very' young fetuses have cal grounds. In regard to etiology, this repaired the combined immunodeficiency disorder could result from abnormal T in several affected children. cell and B cell interaction or a basic stem- Deficient activity of the enzyme.adeno cell defect. sine deaminase (ADA) has been reported in red blood cells and lymphocytes from Secondary Cellular Immune Deficiencies several children with severe combined im munodeficiency. These patients have .the Diminished but not absent cellular im same clinical problems but also may have munity may also accompany lymphoma, bony abnormalities resembling rachitic chronic lymphomatic leukemia, lepro- rosary and flaring of the ends of the ribs matous leprosy, sarcoidosis, congenital on x-ray. Heterozygous carriers of this rubella, primary biliary cirrhosis, protein autosomal recessive defect arc unaffected malnutrition (10), and commonly steroid clinically but can be detected by enzyme or antimetabolite therapy. Some patients studies. Prenatal diagnosis is possible by with these disorders have also had analysis of amniotic fluid fibroblasts. deficient antibody production. Some of these patients have been treated successfully with intermittent transfusions With Immunoglobulin Deficiency: Severe Combined Immunodeficiency of irradiated red blood cells, which are rich in ADA. Deficiency of a second en zyme, nucleoside phosphorylase. has been The primary defect in this disease in described in a few patients with severe most instances is unknown. Successful combined immunodeficiency. Both of therapy with transplanted bone marrow, these enzymes are involved in purine me as well as defects in B and T lymphocyte tabolism (13). function have supported the concept of a Recently several children with CNS stem-cell defect. Many of these patients dysfunction, Candida dermatitis, kerato may have immature T or B cell activity conjunctivitis, and alopecia who had ab and an abnormally functioning thymus, sent skin test and in vitro lymphocyte re suggesting a spectrum of defects to ac sponses to C A lbicans have been count for this syndrome (11, 12). described. One child had absent IgA and Affected, infants begin within their first absence of antibody production when im 6 months to exhibit intractable diarrhea, munized with pneum ococcal poly wasting, candidiasis, persistent morbilli saccharide vaccine at age 3 years. An form rash, and frequent localized and abnormality in biotin-dependent car generalized infections due to almost any boxylase function was suspected on the virus, bacterium, or fungus. Many have basis of metabolic acidosis and excessive died of vaccinia, chickcnpox, or measles. excretion of appropriate metabolites in The thymus cannot be seen on chest x- the urine. Treatment with biotin was asso rays; homograft rejection, dermal delayed ciated with clinical improvement, but im hypersensitivity, and in.vitro lymphocyte mune function remained depressed (14). functions usually arc completely lacking; Immunodeficiency with generalized he and the levels of circulating small lym matopoietic hypoplasia (reticular dysgen phocytes and all immunoglobulins are esia) is a rapidly fatal variant in which very low. both lymphocytes and granulocytes are The disease may appear in families as lacking, perhaps because of a faulty stem an autosomal recessive or X-linked reces cell for both of these elements of the he sive gene defect, or it may occur sporadi matopoietic system. cally. The X-linked recessive type has Although no Specific relationship be tended to have milder clinical and patho tween immunodeficiency syndromes and 5 I'1 Cellular Iinnumity S3 the HLA system has been delected, one Immunodeficiency With patient with SCID who completely lacked Thrombocytopenia and Eczema (Wiskott- HLA-A and B surface antigens has been Adlrich Syndrome) described. It was hypothesized that lack of these antigens adversely affected devel opment of the immune system (15). The. syndrome of eczema, thrombo cytopenic purpura, and recurrent infec tions occurs in boys us an X-linked reces sive trait. As in ataxia-telangiectasia, there arc associated immunoglobulin de Immunodeficiency With Short-Limbed fects (deficient IgM, elevated IgA and Dwarfism . IgE), lymphopenia, blunted cellular im munity, and a propensity to develop ma The clinical and pathologic findings of lignancy. Unlike ataxia-telangiectasia, severe combined immunodeficiency have however, the thymus at autopsy is nor been found in association with dwarfism mal. the antibody response to poly resembling, but not identical to. achon saccharide antigens is abnormal (eg. droplasia. Some affected children have isohemagglutinins are deficient), and pa also had ectodermal dysplasia or neutro tients may suffer severe or lethal infec penia. tions due to viruses and fungi, although A milder form of the disorder has oc bacterial infections tend to predominate curred with cartilage-hair hypoplasia, a early in life. syndrome of short-limbed dwarfism and abnormally finehair. Such children have Mild Combined Immunodeficiency Due to had recurrent bacterial respiratory' infec Enteropathy tions. including pneumonia, and have nearly died of chickenpox. Intestinal lymphangiectasia is charac terized by protein-losing enteropathy with mild fat malabsorption, hvpoalbumi- nemia, edema, panhypogammaglobu Immunodeficiency With Ataxia- linemia, lymphocytopenia, and, in some Telangiectasia patients, failure to thrive. The disease is due to dilated intestinal Children with this autosomal recessive lymphatics which permit the loss of pro syndrome of ataxia and oculocutaneous tein and lymphocytes into the bowel lu telangiectasia often, but not invariably, men. The same condition, although usu develop chronic sinusitis and progressive ally in a milder form, may be associated bronchiectasis. Almost all have an immu with Whipple's disease, regional enteritis, nologic deficiency stale which varies from or constrictive pericarditis. patient to patient but is usually character Most patients with the disorder do not ized by 1) partial immunoglobulin defects have undue susceptibility to infection (most frequently deficient IgA, less com even though cutaneous anergy and failure monly deficient IgE and IgG) and 2) to reject skin grafts are the rule. When ``blunted" cellular immunity manifested frequent infections occur, they tend to be by depressed but not absent lymphocyte mild and confined to the respiratory tract transformation by PHA, prolonged rejec in adults, but In children they may be sys tion of skin grafts, cutaneous anergy in temic. chronic, and lethal. The infecting most cases, and lymphopenia in some organisms are bacteria: apparently, the cases, but no difficulty with candidal, small numbers of normal lymphocytes viral, or other fungal infections, including that are present are adequate to resist vaccinia. The thymus at autopsy has viral and fungal infection. shown consistent abnormalities, including Several patients have experienced ele the absence of Hassall's corpuscles. Lym- vation of serum protein levels and lym phoreticular and other malignancies have phocyte counts, as well as weight gain, on occurred frequently in these children. a diet rich in medium-chain triglycerides. SV IM -'EC nO .V S IX a iIL D U I-X Episodic Lymphopenia With also occurred concomitantly: the inter Lymphocytotoxin (Immunologic Amnesia) relationships between these, the hypo gammaglobulinemia, and the thymoma have not been elucidated. The administration of antilymphocyte serum (ALS) to humans or animals can inhibit both primary and secondary anti THERAPY body responses and suppress the develop ment of cellular immunity. A syndrome of recurrent severe bacte rial and viral infections, eczema, and epi sodic lymphopenia in which the immuno logic findings resemble closely those of ALS-treated animals has been described. Affected children have been capable of initiating primary lymphocyte-dependent responses such as rejection of skin grafts and transformation with PHA, but they have lacked immunologic "memory" so that they do not manifest delayed hyper sensitivity reactions to commonly encoun tered antigens and mount no more than a short, transient, primary type of antibody response on repeated stimulation with the same antigen. There has been a depletion of lymphocytes from thymus-dependent areas of lymph nodes and spleen and a normal (although involuted) thymus in cases studied at autopsy. A complementdependent lymphocytoioxic factor (prob ably antibody) has been found in patients' serums during episodes of lymphopenia. Quantitation of serum immunoglobulins Therapy for the cell-mediated defi ciency syndromes is unsatisfactor)' at best. The most successful form of therapy is bone marrow transplantation. Until re cently. this form of therapy had been re served for children with SC1D and no im mune function so that engraftment would take place. Marrow from an HLA-idemical sibling was required to prevent a graft vs host reaction. Bone marrow trans plantation after irradiation and chemo therapy in syndromes with residual im mune function has now succeeded in other immunodeficiency syndromes, ie, Wiskott-Aldrich. This form of therapy is still experimental, however. If the patient has a combined defect, re placement of immunoglobulins is the only routine therapy available. Treatment of the immune defect per se is often only palliative or designed to augment immune function because the primary defect is un known. The principles of these forms of therapy are summarized elsewhere in these volumes. has shown a consistent abnormality: IgA levels have been markedly elevated. IgM levels have been low or absent, and IgG levels have been normal or elevated. REFERENCES 1. Mollcr G (ed): Natural killer cells. Immun Rev 44. 1979 Immunodeficiency With Thymoma Thymoma is a usually benign tumor which develops in the fourth to eighth decades of life. .Some patients with thymoma have acquired panhypogammaglobulinemia or a partial im munoglobulin defect 1 or 2 years before or after the discovery of the tumor on chest x-ray. Most of these patients have sulfered recurrent infections, particularly bronchitis and pneumonia. Lymphocyto1 penia with skin anerey and prolonged skin graft rejection, aregencrativc anemia, 2. Rocklin RE: Mediators of cellular immunity. In Fundenbcrg HH. Stites OP. Caldwell JL. Wells JV (cds): Basic and Clinical Immunol ogy. Los Altos. Ca: Lange. 1980. p 144 3. Jones JF, Mevskens F L Nagle R: The human thymus: 1. Partial characterization of non-lymphoid cells. Thymus 2:147. 1980 4. Mackaness GB: The mechanism of macro phage activation. In Sludd S (ed): Infectious Agents and Host Reactions. Philadelphia: Saunders. 1970. p 61 5. Zinkernagel RM. Doherty PC: MHC*resiricied cytotoxic T cells; Studies on the biological role of polymorphic major transplantation antigens determining T Cell restnction-specincity. func tion and responsiveness. cosinopenia. and myasthenia gravis have 6. Benaccrraf B. L'nar.ue ER: Textbook of Immu- 5 Ml C c lliiliir Im m unity S5 nologv. Baltimore. William* anJ Wilt (ns. I979.~p. 125 7. Franz ML. Cardia JA. Galant SP: Cutaneous delayed hypersensitivity in a healthy pediatric population: Diagnostic value of dipthcria-tetanus losoids. J Pediatr 88:975. 1976 S. Ross GD. Winchester RJ: Methods for enumerating lymphocyte populations. In Rose NR. Friedman H (eds): Manual of Clinical Immunology. Washington. DC: American So ciety for Microbiology. 1980. p 213 9. Moretta L, Fcrrarini M, Cooper MD: Charac terization of human T cell subpopulations as defined by specific receptors for immunoglob ulins. Contcmp Top Immunobiol 8:19. 1978 10. Carney JM. Warner MS. Borut T. et al: Cellmediated immune defects and infection: A study of hospitalized children. Am J Dis Child 134:824. 1980 11. Cooper MD. Percy DY. Peterson RDA. cl al: The two-component concept of the lymphoid system. In Scrgsma D. Good RA (eds): Immu nologic Deficiency Diseases in Man. New York: The National Foundation. 1968. p 7 12. Pykc KW. Dosch H-M. Ipp MM. ct al: Dem onstration of an intrathymic defect in a case of severe combined immunodeficiency disease. N Engl J Med 293:424. 1975 13. Ammann AJ. Hong R: Disorders of the T cell system. In Sliehm ER. Fuleiniti VA (eds): Im munologic Disorders of Infants and Children. Philadelphia: W.B. Saunders. Inc.. 1980, p 286 14. Cowan MJ. Packman S. Wara DW. ct al: Mul tiple biotin-dependent carboxylase deficiencies associated with defects in T-cell and B-cell im munity. Lancet 2:115. 1979 15. Touraine JL. Betucl H. Souillet G. et al: Com bined immunodeficiency disease associated with absence of cell-surface HLA-A and -B antigens. J Pediatr 93:47. 1978